Compounds and methods of use

ABSTRACT

This disclosure provides compounds and compositions and methods of using those compounds and compositions to treat diseases and disorders associated with excessive transforming growth factor-beta (TGFβ) activity. This disclosure also provides methods of using the compounds in combination with one or more cancer immunotherapies.

Each reference cited in this disclosure is incorporated herein byreference in its entirety.

TECHNICAL FIELD

This disclosure relates generally to compounds and compositions usefulfor treatment (therapy) of conditions associated with excessivetransforming growth factor-beta (TGFβ) activity, and can also be used incombination with one or more cancer immunotherapies.

DETAILED DESCRIPTION

The present invention provides compounds processes for theirpreparation, pharmaceutical compositions containing them, and methods ofusing those compounds and compositions for the treatment of conditionsassociated with excessive transforming growth factor-beta (TGFβ)activity, as described below.

TGFβ belongs to a superfamily of multifunctional proteins that includes,for example, TGFβ1, TGFβ2, and TGFβ3, which are pleiotropic modulatorsof cell growth and differentiation, embryonic and bone development,extracellular matrix formation, hematopoiesis, and immune andinflammatory responses (Roberts and Sporn Handbook of ExperimentalPharmacology (1990) 95:419-58; Massague, et al., Ann. Rev. Cell. Biol.(1990) 6:597-646). For example, TGFβ1 inhibits the growth of many celltypes, including epithelial cells, but stimulates the proliferation ofvarious types of mesenchymal cells. Other members of this superfamilyinclude activin, inhibin, bone morphogenic protein, and Mullerianinhibiting substance. The members of the TGFβ family initiateintracellular signaling pathways leading ultimately to the expression ofgenes that regulate the cell cycle, control proliferative responses, orrelate to extracellular matrix proteins that mediate outside-in cellsignaling, cell adhesion, migration and intercellular communication.

Therefore, inhibitors of the TGFβ intracellular signaling pathway arerecognized as being useful primarily for the treatment offibroproliferative diseases. Fibroproliferative diseases include kidneydisorders associated with unregulated TGFβ activity and excessivefibrosis including glomerulonephritis (GN), such as mesangialproliferative GN, immune GN, and crescentic GN. Other renal conditionsinclude diabetic nephropathy, renal interstitial fibrosis, renalfibrosis in transplant patients receiving cyclosporin, andHIV-associated nephropathy. Collagen vascular disorders includeprogressive systemic sclerosis, polymyositis, scleroderma,dermatomyositis, eosinophilic fasciitis, morphea, or those associatedwith the occurrence of Raynaud's syndrome. Lung fibroses resulting fromexcessive TGFβ activity include adult respiratory distress syndrome,chronic obstructive pulmonary disease (COPD), idiopathic pulmonaryfibrosis, and interstitial pulmonary fibrosis often associated withautoimmune disorders, such as systemic lupus erythematosus andscleroderma, chemical contact, or allergies. Another autoimmune disorderassociated with fibroproliferative characteristics is rheumatoidarthritis. Fibroproliferative conditions can be associated with surgicaleye procedures. Such procedures include retinal reattachment surgeryaccompanying proliferative vitreoretinopathy, cataract extraction withintraocular lens implantation, and post glaucoma drainage surgery.

In addition, members of the TGFβ family are associated with theprogression of various cancers, M. P. de Caestecker, E. Piek, and A. B.Roberts, J. National Cancer Inst., 92(17), 1388-1402 (2000) and membersof the TGFβ family are expressed in large amounts in many tumors.Derynck, Trends Biochem. Sci., 1994, 19, 548-553. For example, it hasbeen found that TGFβ1 inhibits the formation of tumors, probably byinhibition of the proliferation of non-transformed cells. However, oncea tumor forms, TGFβ 1 promotes the growth of the tumor. N. Dumont and C.L. Arteaga, Breast Cancer Res., Vol. 2, 125-132 (2000). Thus, inhibitorsof the TGFβ pathway are also recognized as being useful for thetreatment of many forms of cancer, such as lung cancer, skin cancer, andcolorectal cancer. In particular, they are considered to be useful forthe treatment of cancers of the breast, pancreas, and brain, includingglioma.

For simplicity and illustrative purposes, the principles of theinvention are described by referring mainly to specific illustrativeembodiments thereof. In addition, in the following description, numerousspecific details are set forth in order to provide a thoroughunderstanding of the invention. It will be apparent however, to one ofordinary skill in the art, that the invention may be practiced withoutlimitation to these specific details. In other instances, well knownmethods and structures have not been described in detail so as not tounnecessarily obscure the invention.

In additional to the compounds that are specifically illustrated,applicants also intend to include any and all stereoisomers, includinggeometric isomers (cis/trans or E/Z isomers), tautomers, salts,N-oxides, and solvates of the compounds and such alternatives also canbe used in the disclosed methods.

Compounds

The compounds disclosed herein fall within formula (I):

-   -   wherein Ar₁ represents an optionally substituted aryl (such as        an optionally substituted phenyl), or an optionally substituted        heteroaryl (such as an optionally substituted pyridyl);    -   A represents H, halogen, amino, alkyl, alkenyl, alkynyl, alkoxy,        cycloalkyl, cycloalkenyl, or heterocyclyl wherein the amino,        alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, or heterocyclyl can        also be substituted;    -   Z represents H, halogen, amino, alkyl, alkenyl, alkynyl, alkoxy,        cycloalkyl, or heterocyclyl wherein the amino, alkyl, alkenyl,        alkynyl, alkoxy, cycloalkyl, or heterocyclyl can also be        substituted;    -   Ar₂ represents an optionally substituted aryl (such as an        optionally substituted phenyl), or an optionally substituted        heteroaryl (such as an optionally substituted pyridyl, or an        optionally substituted pyrazolyl).

The invention also contemplates pharmaceutically acceptable salts ofsuch compounds.

In some embodiments, Ar_(t) in the compounds of formula (I) can be oneof

-   -   wherein X is N or C—R₆ and wherein each of R₁, R₂, R₃, R₄, R₅,        and R₆ is independently H, halogen, or alkyl, where the alkyl        can also be substituted.

In one embodiment of the compounds of formula (I). Ar₁ is

-   -   wherein each R₁, R₂, R₃, R₄, and R₅ is independently selected        from H, halogen, or alkyl, where the alkyl can also be        substituted. In some embodiments, the alkyl is substituted with        a substituent selected from the group consisting of halogen,        hydroxy, amino, cyano, mercapto, alkoxy, aryloxy, nitro, oxo,        carboxyl, carbamoyl, cycloalkyl, aryl, heterocycloalkyl,        heteroaryl, alkylsulfonyl, arylsulfonyl, and —OCF₃.

In some embodiments, R₁, R₂, R₃, R₄, and R₅ independently are selectedfrom the group consisting of halogen, hydroxy, amino, cyano, alkoxy,nitro, mercapto, carboxyl, carbamoyl, alkyl, substituted alkyl. —OCF₃,alkylsulfonyl, arylsulfonyl, heterocyclyl, and heteroaryl.

Thus, one subset of structures for Ar₁ include:

In another embodiment of the compounds of formula (I), Ar₁ is selectedfrom the group consisting of the following structures:

-   -   wherein each of R₁, R₂, R₃, R₄, and R₅ is independently H,        halogen, or alkyl, where the alkyl can also be substituted.

Thus, another subset of structures for Ar₁ include the followingstructures:

One subset of structures for Ar₂ include the following structures:

-   -   wherein R₇ is alkyl, or a substituted alkyl. One particular        substituted alkyl for R₇, is

-   -    wherein R₈ and R₉ are independently selected from H, or alkyl,        and where the alkyl can also be substituted; or R₈ and R₉ can be        joined together to form an optionally substituted 3-8 membered        heterocyclic ring (heterocyclyl).

In particular embodiments. Ar₂ can be

-   -   wherein X₁ and X are independently N, or CH, and where R₇ is        alkyl, substituted alkyl, cycloalkyl or heterocyclyl. In one        such embodiment, X₁ is N, X is CH, and R₇ is

-   -    wherein R₈ and R₉ are independently selected from H, or alkyl,        and where the alkyl can also be substituted; or wherein R₈ and        R₉ can be joined together to form an optionally substituted 3-8        membered heterocyclic (heterocyclyl) ring. In another such        embodiment, X₁ is N, X is CH, and R₇ is oxazol-2-yl or        thiazol-2-yl.

Table 1 below presents a variety of suitable substituted alkyls for useas R₇ in the formulae above.

TABLE 1

In particular embodiments, R₇ is selected from the group consisting of

Another subset of structures for Ar₂ include the following structures;

wherein R₇ is H or alkyl.

In particular embodiments, Ar₂ can be a bicyclic heteroaryl selectedfrom the group consisting of

Table 2 below presents a variety of suitable substituents for use as Aor Z in the formulae above.

TABLE 2 F, Cl, Br, —CH₃, CF₃ —NH₂,

In particular embodiments, A is selected from the group consisting of

In particular embodiments, Z is H.

In one embodiment, the compound of formula (I) is of the formulae (A),(B), (C), and (D):

or a salt thereof, wherein A, Z. Ar₂. R₁, R₂, R₃, and R₄ are asdescribed for formula (I). In some preferred embodiments, the compoundis of formula (A). In other preferred embodiments, the compound is offormula (B).

In some embodiments, the compound of formula (A) is of the formulae(Aa), (Ab), (Ac), (Ad), (Ae) and (Af):

or a salt thereof, where in each of (Aa), (Ab), (Ac), (Ad), (Ae) and(Af), the substituents A, R₁, R₂, R₃, R₄, R₅ and R₇, where present, areas described for formula (I) or any applicable variation thereof. Inpreferred embodiments, the compound is of formula (Aa).

In some embodiments, the compound of formula (Aa) is of the formulae(Aa-1), (Aa-2). (Aa-3), (Aa-4), (Aa-5). (Aa-6), (Aa-7), (Aa-8), and(Aa-9):

or a salt thereof, where in each of (Aa-1), (Aa-2), (Aa-3). (Aa-4),(Aa-5), (Aa-6), (Aa-7). (Aa-8), and (Aa-9), the substituents A and R₇are as described for formula (I), or any applicable variation thereof.In preferred embodiments, the compound is of formula (Aa-1).

In some embodiments, the compound of formula (Aa-1) is of the formulae(Aa-1a), (Aa-1b), (Aa-1c), (Aa-1d), (Aa-1e), (Aa-1f), and (Aa-1g):

or a salt thereof, where in each of (Aa-1a), Aa-1 b), (Aa-1c), (Aa-1d),(Aa-1e), (Aa-1f), and (Aa-1g), the substituent R₇ is as described forformula (I), or any applicable variation thereof. In preferredembodiments, R₇ is

wherein R₈ and R₉ are independently selected from H. or alkyl, and wherethe alkyl can also be substituted; or R₈ and R₉ can be joined togetherto form an optionally substituted 3-8 membered heterocyclic ring(heterocyclyl). In particular embodiments, R₇ is selected from the groupconsisting of

In some embodiments, the compound is of the formula (Aa-1a), wherein R₇is

In some embodiments, the compound is of the formula (Aa-1b), wherein R₇is

In some embodiments, the compound is of the formula (Aa-1c), wherein R₇is

In some embodiments, the compound is of the formula (Aa-1d), wherein R₇is

In some embodiments, the compound is of the formula (Aa-1e), wherein R;is

In some embodiments, the compound is of the formula (Aa-1 f), wherein R₇is

In some embodiments, the compound is of the formula (Aa-1g), wherein R₇is

In some embodiments, the compound of formulae (Ab), (Ac), (Ad), (Ae) and(Af) is of the formulae (Ab-1), (Ac-1), (Ad-1), (Ae-1) and (Af-1):

or a salt thereof, where in each of (Ab-1), (Ac-1), (Ad-1). (Ae-1) and(Af-1), the substituents A and R₇, where present, are as described forformula (I) or any applicable variation thereof. In particularembodiments, R₇ is H or CH₃.

In some embodiments, the compound is of formula (Ab-1), wherein A is

In some embodiments, the compound is of formula (Ac-1), wherein A is

In some embodiments, the compound is of formula (Ad-1), wherein A is

In some embodiments, the compound is of formula (Ae-1), wherein A is

In some embodiments, the compound is of formula (Af-1), wherein A is

In some embodiments, the compound of formula (B) is of the formulae(Ba), (Bb), (Bc), (Bd), (Be) and (Bf):

or a salt thereof, where in each of (Ba). (Bb), (Bc), (Bd), (Be) and(Bf), the substituents A. R₁, R₂, R₃, R₄, and R₇, where present, are asdescribed for formula (I) or any applicable variation thereof. Inparticular embodiments, R₇ is H or CH₃.

In some embodiments, the compound of formulae (Ba), (Bb), (Bc), (Bd).(Be), and (Bf) is of the formulae (Ba-1), (Bb-1), (Bc-1), (Bd-1), (Be-1)and (Bf-1):

or a salt thereof, where in each of (Ba-1), (Bb-1), (Bc-1), (Bd-1),(Be-1) and (Bf-1), the substituents A and R₇, where present, are asdescribed for formula (I) or any applicable variation thereof. Inparticular embodiments, R₇ is H or CH₃.

The embodiments and variations described herein are suitable forcompounds of any formulae detailed herein, where applicable. As such,variations of formula (I) detailed throughout where applicable apply toformulae (A), (B), (C), and (D), the same as if each and every variationwere specifically listed for formulae (A), (B), (C), and (D). Variationsof formulae (A), (B), (C), and (D), detailed throughout, whereapplicable, apply to formulae (Aa). (Ab). (Ac), (Ad), (Ae), and (Af),the same as if each and every variation were specifically listed forformulae (Aa), (Ab), (Ac), (Ad), (Ae), and (Af). Variations of formulae(Aa), (Ab), (Ac), (Ad), (Ae), and (Af), detailed throughout, whereapplicable, apply to formulae (Aa-1), (Aa-2), (Aa-3), (Aa-4), (Aa-5),(Aa-6), (Aa-7), (Aa-8), and (Aa-9), the same as if each and everyvariation were specifically listed for formulae (Aa-1). (Aa-2), (Aa-3),(Aa-4), (Aa-5), (Aa-6). (Aa-7), (Aa-8), and (Aa-9). Variations offormulae (Aa-1), (Aa-2), (Aa-3). (Aa-4), (Aa-5), (Aa-6). (Aa-7), (Aa-8),and (Aa-9), detailed throughout, where applicable, apply to formulae(Aa-1a), (Aa-1b), (Aa-1c), (Aa-1d), (Aa-1e), (Aa-1f), and (Aa-1g), thesame as if each and every variation were specifically listed forformulae (Aa-1a), (Aa-1b), (Aa-1c), (Aa-1d), (Aa-1e), (Aa-1f), and(Aa-1g). Variations of formulae (Ab), (Ac), (Ad), (Ae), and (Af),detailed throughout, where applicable, apply to formulae (Ab-1), (Ac-1),(Ad-1), (Ae-1), and (Af-1), the same as if each and every variation werespecifically listed for formulae (Ab-1), (Ac-1), (Ad-1), (Ae-1), and(Af-1). Variations of formula (B), detailed throughout, whereapplicable, apply to formulae (Ba), (Bb), (Bc), (Bd), (Be), and (Bf),the same as if each and every variation were specifically listed forformulae (Ba), (Bb), (Bc), (Bd), (Be), and (Bf). Variations of formula(Ba), (Bb), (Bc), (Bd), (Be), and (Bf), detailed throughout, whereapplicable, apply to formulae (Ba-1), (Bb-1), (Bc-1), (Bd-1), (Be-1),and (Bf-1), the same as if each and every variation were specificallylisted for formulae (Ba-1), (Bb-1), (Bc-1), (Bd-1), (Be-1), and (Bf-1).

Particular compounds described below are not intended to be limiting;rather, these embodiments and variations are intended to provideexamples of compounds within the scope of formula (I).

Definitions

“Alkyl” (monovalent) and “alkylene” (divalent) when used alone or aspart of another term (e.g., alkoxy) mean a branched or unbranched,saturated aliphatic hydrocarbon group, having up to 12 carbon atomsunless otherwise specified. Examples of particular alkyl groups include,but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl,iso-butyl, sec-butyl, tert-butyl, n-pentyl, 2-methylbutyl,2,2-dimethylpropyl, n-hexyl, 2-methylpentyl, 2,2-dimethylbutyl,n-heptyl, 3-heptyl, 2-methylhexyl, and the like. The term, “lower,” whenused to modify alkyl or alkylene, means 1 to 4 carbon atoms, so that,e.g., the terms “lower alkyl,” “C₁-C₄ alkyl” and “alkyl of 1 to 4 carbonatoms” are synonymous and may be used interchangeably to mean methyl,ethyl, i-propyl, isopropyl, 1-butyl, sec-butyl or t-butyl. Examples ofalkylene groups include, but are not limited to, methylene, ethylene,n-propylene, n-butylene and 2-methyl-butylene.

The term “substituted alkyl” refers to an alkyl moiety havingsubstituents replacing one or more hydrogens on one or more (often nomore than four) carbon atoms of the hydrocarbon backbone. Suchsubstituents are independently selected from the group consisting of:halogens (e.g., iodo (I), bromo (Br), chloro (Cl), or fluoro (F),particularly fluoro (F)), hydroxy, amino, cyano, mercapto, alkoxy (suchas a C₁-C₆ alkoxy, or a lower (C₁-C₄) alkoxy, e.g., methoxy or ethoxy toyield an alkoxyalkyl), aryloxy (such as phenoxy to yield anaryloxyalkyl), nitro, oxo ((═O), e.g., to form a carbonyl), carboxyl(which is actually the combination of an oxo and hydroxy substituent ona single carbon atom), carbamoyl (an aminocarbonyl such as NR₂C(O)—,which is the substitution of an oxo and an amino (as defined hereafter)on a single carbon atom), cycloalkyl (e.g., to yield a cycloalkylalkyl),aryl (resulting for example in an aralkyl such as benzyl orphenylethyl), heterocycloalkyl (e.g., resulting in aheterocycloalkylalkyl), heteroaryl (e.g., resulting in aheteroarylalkyl), alkylsulfonyl (including lower alkylsulfonyl such asmethylsulfonyl), arylsulfonyl (such as phenylsulfonyl), and —OCF₃ (whichis a halogen substituted alkoxy).

The invention further contemplates that several of these alkylsubstituents, including specifically alkoxy, cycloalkyl, aryl,heterocyclyalkyl and heteroaryl, themselves can be optionally furthersubstituted as defined in connection with each of their respectivedefinitions provided below.

In addition, as noted above, certain alkyl substituent moieties resultfrom a combination of such substitutions on a single carbon atom. Forexample, an ester moiety, e.g., an alkoxycarbonyl such asmethoxycarbonyl, or tert-butoxycarbonyl (Boc) results from such multiplesubstitutions. In particular, methoxycarbonyl is a substituted alkylthat results from the substitution, on a methyl group (—CH₃), of both anoxo (═O) and an unsubstituted alkoxy, e.g., a methoxy (CH₃—O—).Tert-butoxycarbonyl (Boc) results from the substitution on a methylgroup (—CH₃) of both an oxo (═O) and an unsubstituted alkoxy, e.g., atert-butoxy ((CH₃)₃C—O—). In both cases, the oxo substituent and theunsubstituted alkoxy substituent replace all three hydrogens on themethyl group. Similarly, an amide moiety, e.g., an alkylaminocarbonyl,such as dimethylaminocarbonyl or methylaminocarbonyl, is a substitutedalkyl that results from the substitution on a methyl group (—CH₃) ofboth an oxo (═O) and a mono-substituted alkylamino or, a di-substitutedalkylamino, e.g., dimethylamino (—N—(CH)₂), or methylamino (—NH—(CH₃)),replacing the three methyl hydrogens (similarly an arylaminocarbonylsuch as diphenylaminocarbonyl is a substituted alkyl that results fromthe substitution on a methyl group (—CH₃) of both an oxo (═O) and amono-substituted aryl(phenyl)amino). Exemplary substituted alkyl groupsfurther include cyanomethyl, nitromethyl, hydroxyalkyls such ashydroxymethyl, trityloxymethyl, propionyloxymethyl, aminoalkyls such asaminomethyl, carboxylalkyls such as carboxymethyl, carboxyethyl,carboxypropyl, 2,3-dichloropentyl, 3-hydroxy-5-carboxyhexyl, acetyl(e.g., an alkanoyl, where in the case of acetyl the two hydrogen atomson the —CH₂ portion of an ethyl group are replaced by an oxo (═O)),2-aminopropyl, pentachlorobutyl, trifluoromethyl, methoxyethyl,3-hydroxypentyl, 4-chlorobutyl, 1,2-dimethyl-propyl, pentafluoroethyl,alkyloxycarbonylmethyl, allyloxycarbonylaminomethyl, carbamoyloxymethyl,methoxymethyl, ethoxymethyl, t-butoxymethyl, acetoxymethyl,chloromethyl, bromomethyl, iodomethyl, trifluoromethyl, 6-hydroxyhexyl,2,4-dichloro (n-butyl), 2-amino (iso-propyl), cycloalkylcarbonyl (e.g.,cuclopropylcarbonyl) and 2-carbamoyloxyethyl. Particular substitutedalkyls are substituted methyl groups. Examples of substituted methylgroup include groups such as hydroxymethyl, protected hydroxymethyl(e.g., tetrahydropyranyloxymethyl), acetoxymethyl, carbamoyloxymethyl,trifluoromethyl, chloromethyl, carboxymethyl, carboxyl (where the threehydrogen atoms on the methyl are replaced, two of the hydrogens arereplaced by an oxo (═O) and the other hydrogen is replaced by a hydroxy(—OH)), tert-butoxycarbonyl (where the three hydrogen atoms on themethyl are replaced, two of the hydrogens are replaced by an oxo (═O)and the other hydrogen is replaced by a tert-butoxy (—O—C(CH₃)₃),bromomethyl and iodomethyl. When the specification and especially theclaims refer to a particular substituent for an alkyl, that substituentcan potentially occupy one or more of the substitutable positions on thealkyl. For example, reciting that an alkyl has a fluoro substituent,would embrace mono-, di-, and possibly a higher degree of substitutionon the alkyl moiety.

“Alkoxy” is an —O-alkyl. A “substituted alkoxy” is an —O-substitutedalkyl, where the alkyl portion of the alkoxy is similarly substitutedwith groups as set forth above for alkyl. One substituted alkoxy isacetoxy where two of the hydrogens in ethoxy (e.g., —O—CH₂—CH₃) arereplaced by an oxo, i.e., (═O), to yield —O—C(O)—CH₃; anothersubstituted alkoxy is an aralkoxy where one of the hydrogens in thealkoxy is replaced by an aryl. One such example is benzyloxy where oneof the hydrogens on methoxy is replaced with phenyl. Another substitutedalkoxy is a carbamate where two of the hydrogens for example on methoxy(e.g., —O—CH₃) are replaced by oxo (═O) and the other hydrogen isreplaced by an amino (e.g., —NH₂, —NHR or —NRR) to yield, for example,—O—C(O)—NH₂. A lower alkoxy is an —O-lower alkyl.

“Alkenyl” (monovalent) and “alkenylene” (divalent) when alone or as partof another term mean an unsaturated hydrocarbon group containing one ormore carbon-carbon double bonds, typically 1 or 2 carbon-carbon doublebonds, and usually only one double bond. The hydrocarbon group may belinear or branched and may have at least 2 and up to 12 carbon atomsunless otherwise specified. Representative alkenyl groups include, byway of example, vinyl, allyl, isopropenyl, but-2-enyl, n-pent-2-enyl,and n-hex-2-enyl.

The terms “substituted alkenyl” and “substituted alkenylene” refer toalkenyl and alkenylene moieties having substituents replacing one ormore hydrogens on one or more (often no more than four) carbon atoms ofthe hydrocarbon backbone. Such substituents are independently selectedfrom the group consisting of: halo (e.g., I, Br, Cl, F), hydroxy, amino,cyano, alkoxy (such as C₁-C₆ alkoxy), aryloxy (such as phenoxy), nitro,mercapto, carboxyl, oxo, carbamoyl, cycloalkyl, aryl, heterocyclyl,heteroaryl, alkylsulfonyl, arylsulfonyl and —OCF₃.

“Alkynyl” means a monovalent unsaturated hydrocarbon group containingone or more carbon-carbon triple bonds, typically only 1 carbon-carbontriple bond, which may be linear or branched and which may have at least2 and up to 12 carbon atoms unless otherwise specified. Representativealkynyl groups include, by way of example, ethynyl, propargyl, andbut-2-ynyl.

“Cycloalkyl,” when alone or as part of another term, means a saturatedor partially unsaturated cyclic aliphatic hydrocarbon group (carbocyclegroup), having at least 3 and up to 12 carbon atoms unless otherwisespecified, such as cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl,and further includes polycyclic, including fused cycloalkyls such as1,2,3,4-tetrahydonaphthalenyls (1,2,3,4-tetrahydonaphthalen-1-yl, and1,2,3,4-tetrahydonaphthalen-2-yl), indanyls (indan-1yl, and indan-2-yl),isoindenyls (isoinden-1-yl, isoinden-2-yl, and isoinden-3-yl) andindenyls (inden-1-yl, inden-2-yl and inden-3-yl). A lower cycloalkyl hasfrom 3 to 6 carbon atoms and includes cyclopropyl, cyclobutyl,cyclopentyl and cyclohexyl.

The term “substituted cycloalkyl” refers to a cycloalkyl moiety havingsubstituents replacing one or more hydrogens on one or more (often nomore than four) carbon atoms of the hydrocarbon backbone. Suchsubstituents are independently selected from the group consisting of:halo (e.g., I, Br, Cl, F), hydroxy, amino, cyano, alkoxy (such as C₁-C₆alkoxy), substituted alkoxy, aryloxy (such as phenoxy), nitro, mercapto,carboxyl, oxo, carbamoyl, alkyl, substituted alkyls such astrifluoromethyl, aryl, substituted aryls, heterocyclyl, heteroaryl,alkylsulfonyl, arylsulfonyl and —OCF₃. When the specification andespecially the claims refer to a particular substituent for acycloalkyl, that substituent can potentially occupy one or more of thesubstitutable positions on the cycloalkyl. For example, reciting that acycloalkyl has a fluoro substituent, would embrace mono-, di-, and ahigher degree of fluoro substitution on the cycloalkyl moiety.

“Amino” denotes primary (i.e., —NH₂), secondary (i.e., —NHR) andtertiary (i.e., —NRR) amines, where the R groups can be the same ordifferent and can be selected from a variety of moieties, usually analkyl, an aryl, or a cycloalkyl, and especially a lower alkyl and anaryl (phenyl). Secondary and tertiary aminos thus include alkylamino,dialkylamino, arylamino, diarylamino, aralkylamino and diaralkylamino.Particular secondary and tertiary amines are methylamino, ethylamino,propylamino, isopropylamino, phenylamino, benzylamino dimethylamino,diethylamino, dipropylamino and disopropylamino. A substituted aminoincludes an amino where the alkyl, aryl, or cycloalkyl is/aresubstituted with halo (e.g., I, Br, Cl, F), hydroxy, cyano, alkoxy (suchas C₁-C₆ alkoxy), aryloxy (such as phenoxy), nitro, mercapto, carboxyl,oxo, carbamoyl, heterocyclyl, heteroaryl, alkylsulfonyl, arylsulfonyland —OCF₃

“Aryl,” when used alone or as part of another term, means an aromaticcarbocyclic group whether or not fused having the number of carbon atomsdesignated, or if no number is designated, from 6 up to 14 carbon atoms.Particular aryl groups include phenyl, naphthyl, biphenyl,phenanthrenyl, naphthacenyl, and the like (see e. g. Lang's Handbook ofChemistry (Dean, J. A., ed) 13^(th) ed. Table 7-2 [1985]). Phenyl andnaphthyl groups are generally preferred and phenyl is by far the mostcommonly employed aryl.

The term “substituted aryl,” such as substituted phenyl, refers to anaryl moiety having substituents replacing one or more hydrogens on oneor more (usually no more than six) carbon atoms of the aromatichydrocarbon core. Such substituents are independently selected from thegroup consisting of: halogens (e.g., I, Br, Cl, F), hydroxy, amino,cyano, alkoxy (such as C₁-C₆ alkoxy and particularly lower alkoxy),substituted alkoxy, aryloxy (such as phenoxy), nitro, mercapto,carboxyl, carbamoyl, alkyl, substituted alkyl (such as trifluoromethyl),aryl, —OCF₃, alkylsulfonyl (including lower alkylsulfonyl),arylsulfonyl, heterocyclyl and heteroaryl. Examples of such substitutedphenyls include but are not limited to a mono- or di (halo) phenyl groupsuch as 2-chlorophenyl, 2-bromophenyl, 4-chlorophenyl,2,6-dichlorophenyl, 2,5-dichlorophenyl, 3,4-dichlorophenyl,3-chlorophenyl, 3-bromophenyl, 4-bromophenyl, 3,4-dibromophenyl,3-chloro-4-fluorophenyl, 2-fluorophenyl; 3-fluorophenyl, 4-fluorophenyl,a mono- or di (hydroxy) phenyl group such as 4-hydroxyphenyl,3-hydroxyphenyl, 2,4-dihydroxyphenyl, the protected-hydroxy derivativesthereof; a nitrophenyl group such as 3- or 4-nitrophenyl; a cyanophenylgroup, for example, 4-cyanophenyl; a mono- or di (lower alkyl) phenylgroup such as 4-methylphenyl, 2,4-dimethylphenyl, 2-methylphenyl,4-(iso-propyl)phenyl, 4-ethylphenyl, 3-(n-propyl) phenyl; a mono or di(alkoxy) phenyl group, for example, 3,4-dimethoxyphenyl,3-methoxy-4-benzyloxyphenyl, 3-methoxy-4-(1-chloromethyl)benzyloxy-phenyl, 3-ethoxyphenyl, 4-(isopropoxy) phenyl, 4-(t-butoxy)phenyl, 3-ethoxy-4-methoxyphenyl; 3- or 4-trifluoromethylphenyl; a mono-or dicarboxyphenyl or (protected carboxy) phenyl group such4-carboxyphenyl; a mono- or di (hydroxymethyl) phenyl or (protectedhydroxymethyl) phenyl such as 3-(protected hydroxymethyl) phenyl or3,4-di (hydroxymethyl) phenyl; a mono- or di (aminomethyl) phenyl or(protected aminomethyl) phenyl such as 2-(aminomethyl) phenyl or 2,4-(protected aminomethyl) phenyl; or a mono- or di(N-(methylsulfonylamino)) phenyl such as 3-(N-methylsulfonylamino)phenyl. Also, the substituents, such as in a di-substituted or highersubstituted phenyl group, can be the same or different, for example,3-methyl-4-hydroxyphenyl, 3-chloro-4-hydroxyphenyl,2-methoxy-4-bromophenyl, 4-ethyl-2-hydroxyphenyl,3-hydroxy-4-nitrophenyl, 2-hydroxy-4-chlorophenyl. When thespecification and especially the claims refer to a particularsubstituent for an aryl, that substituent can potentially occupy one ormore of the substitutable positions on the aryl. For example, recitingthat an aryl has a fluoro substituent, would embrace mono-, di-, tri,tetra and a higher degree of substitution on the aryl moiety. Fused arylrings may also be substituted with the substituents specified herein,for example with 1, 2 or 3 substituents, in the same manner assubstituted alkyl groups. The terms aryl and substituted aryl do notinclude moieties in which an aromatic ring is fused to a saturated orpartially unsaturated aliphatic ring.

“Aryloxy” is —O-aryl. A “substituted aryloxy” is —O-substituted aryl,where the suitable substituents are those described for a substitutedaryl.

“Heterocyclic ring,” “heterocyclic group,” “heterocyclic,”“heterocycle,” “heterocyclyl,” “heterocycloalkyl” or “heterocycle,”alone and when used as a moiety in a complex group, are usedinterchangeably and refer to any mono-, bi-, or tricyclic, saturated orunsaturated, non-aromatic hetero-atom-containing ring system having thenumber of atoms designated, or if no number is specifically designatedthen from 5 to about 14 atoms in the ring, where the ring atoms arecarbon and at least one heteroatom and usually not more than fourheteroatoms (i.e., nitrogen, sulfur or oxygen). Included in thedefinition are any bicyclic groups where any of the above heterocyclicrings are fused to an aromatic ring (i.e., an aryl (e.g., benzene) or aheteroaryl ring). In a particular embodiment, the group incorporates 1to 4 heteroatoms. Typically, a 5-membered ring has 0 to 1 double bondsand a 6- or 7-membered ring has 0 to 2 double bonds and the nitrogen orsulfur heteroatoms may optionally be oxidized (e.g. NO, SO, SO₂), andany nitrogen heteroatom may optionally be quaternized. Particularunsubstituted non-aromatic heterocycles include morpholinyl(morpholino), pyrrolidinyls, oxiranyl, indolinyls, 2,3-dihydoindolyl,isoindolinyls, 2,3-dihydoisoindolyl, tetrahydroquinolinyls,tetrahydroisoquinolinyls, oxetanyl, tetrahydrofuranyls,2,3-dihydrofuranyl, 2H-pyranyls, tetrahydropyranyls, aziridinyls,azetidinyls, 1-methyl-2-pyrrolyl, piperazinyls, and piperidinyls.

The term “substituted heterocyclo” refers to heterocyclo moieties havingsubstituents replacing one or more hydrogens on one or more (usually nomore than six) atoms of the heterocyclo backbone. Such substituents areindependently selected from the group consisting of: halo (e.g., I, Br,Cl, F), hydroxy, amino, cyano, alkoxy (such as C₁-C₆ alkoxy),substituted alkoxy, aryloxy (such as phenoxy), nitro, carboxyl, oxo,carbamoyl, alkyl, substituted alkyl (such as trifluoromethyl), —OCF₃,aryl, substituted aryl, alkylsulfonyl (including lower alkylsulfonyl),and arylsulfonyl. When the specification and especially the claims referto a particular substituent for a heterocycloalkyl, that substituent canpotentially occupy one or more of the substitutable positions on theheterocycloalkyl. For example, reciting that a heterocycloalkyl has afluoro substituent, would embrace mono-, di-, tri, tetra, and a higherdegree of substitution on the heterocycloalkyl moiety.

“Heteroaryl,” alone and when used as a moiety in a complex group, refersto any mono-, bi-, or tricyclic aromatic ring system having the numberof atoms designated, or if no number is specifically designated then atleast one ring is a 5-, 6- or 7-membered ring and the total number ofring atoms is from 5 to about 14 and containing from one to fourheteroatoms selected from the group consisting of nitrogen, oxygen, andsulfur. Included in the definition are any bicyclic groups where any ofthe above embraced or below-noted heteroaryl rings are fused to abenzene ring or to a heterocycle ring. The following ring systems areexamples of the heteroaryl groups denoted by the term “heteroaryl”;thienyls (alternatively called thiophenyl), furyls, imidazolyls,pyrazolyls, thiazolyls, isothiazolyls, oxazolyls, isoxazolyls,triazolyls, thiadiazolyls, oxadiazolyls, tetrazolyls, thiatriazolyls,oxatriazolyls, pyridyls (including 1H-pyrrolo[2,3-b]pyridyls, and3H-imidazo[4,5-b]pyridyls), pyrimidinyls (e.g., pyrimidin-2-yl),pyrazinyls, pyridazinyls, thiazinyls, oxazinyls, triazinyls,thiadiazinyls, oxadiazinyls, dithiazinyls, dioxazinyls, oxathiazinyls,tetrazinyls, thiatriazinyls, oxatriazinyls, dithiadiazinyls,imidazolinyls, dihydropyrimidyls, tetrahydropyrimidyls, tetrazolo [1,5-b] pyridazinyl and purinyls. The following benzo-fused derivatives,for example benzoxazolyls, benzofuryls, benzothienyls, benzothiazolyls,benzothiadiazolyl, benzotriazolyls, benzoimidazolyls, isoindolyls,indazolyls, indolizinyls, indolyls, naphthyridines, pyridopyrimidines,phthalazinyls, quinolyls, isoquinolyls, and quinazolinyls are alsoembraced under the definition of heteroaryl.

The term “substituted heteroaryl” refers to heteroaryl moieties (such asthose identified above, such as substituted pyridyl, or substitutedpyrazolyl) having substituents replacing one or more hydrogens on one ormore (usually no more than six) atoms of the heteroaryl backbone. Suchsubstituents are independently selected from the group consisting of:halogen (e.g., I, Br, Cl, F), hydroxy, amino, cyano, alkoxy (such asC₁-C₆ alkoxy), aryloxy (such as phenoxy), nitro, mercapto, carboxyl,carbamoyl, alkyl, substituted alkyl (such as trifluoromethyl), —OCF₃,aryl, substituted aryl, alkylsulfonyl (including lower alkylsulfonyl),and arylsulfonyl. When the specification and especially the claims referto a particular substituent for a heteroaryl, that substituent canpotentially occupy one or more of the substitutable positions on theheteroaryl. For example, reciting that a heteroaryl has a fluorosubstituent, would embrace mono-, di-, tri, tetra, and a higher degreeof substitution on the heteroaryl moiety.

Examples of “heteroaryls” (including “substituted heteroaryls”) include;1H-pyrrolo[2,3-b]pyridine; 1,3-thiazol-2-yl;4-(carboxymethyl)-5-methyl-1,3-thiazol-2-yl; 1,2,4-thiadiazol-5-yl;3-methyl-1,2,4-thiadiazol-5-yl; 1,3,4-triazol-5-yl;2-methyl-1,3,4-triazol-5-yl; 2-hydroxy-1,3,4-triazol-5-yl;2-carboxy-4-methyl-1,3,4-triazol-5-yl; 1,3-oxazol-2-yl;1,3,4-oxadiazol-5-yl; 2-methyl-1,3,4-oxadiazol-5-yl;2-(hydroxymethyl)-1,3,4-oxadiazol-5-yl; 1,2,4-oxadiazol-5-yl;1,3,4-thiadiazol-5-yl; 2-thiol-1,3,4-thiadiazol-5-yl;2-(methylthio)-1,3,4-thiadiazol-5-yl; 2-amino-1,3,4-thiadiazol-5-yl;1H-tetrazol-5-yl; 1-methyl-1H-tetrazol-5-yl;1-(1-(dimethylamino)eth-2-yl)-1H-tetrazol-5-yl;1-(carboxymethyl)-1H-tetrazol-5-yl; 1-(methylsulfonicacid)-1H-tetrazol-5-yl; 2-methyl-1H-tetrazol-5-yl; 1,2,3-triazol-5-yl;1-methyl-1,2,3-triazol-5-yl; 2-methyl-1,2,3-triazol-5-yl;4-methyl-1,2,3-triazol-5-yl; pyrid-2-yl N-oxide;6-methoxy-2-(n-oxide)-pyridaz-3-yl; 6-hydroxypyridaz-3-yl;1-methlpyrid-2-yl; 1-methylpyrid-4-yl; 2-hydroxypyrimid-4-yl;1H-Pyrazolo[3,4-d]pyrimidine; 1,4,5,6-tetrahydro-5,6-dioxo-4-methyl-as-triazin-3-yl;1,4,5,6-tetrahydro-4-(formylmethyl)-5,6-dioxo-as-triazin-3-yl;2,5-dihydro-5-oxo-6-hydroxy-astriazin-3-yl;2,5-dihydro-5-oxo-6-hydroxy-as-triazin-3-yl;2,5-dihydro-5-oxo-6-hydroxy-2-methyl-astriazin-3-yl;2,5-dihydro-5-oxo-6-hydroxy-2-methyl-as-triazin-3-yl;2,5-dihydro-5-oxo-6-methoxy-2-methyl-as-triazin-3-yl;2,5-dihydro-5-oxo-as-triazin-3-yl;2,5-dihydro-5-oxo-2-methyl-as-triazin-3-yl;2,5-dihydro-5-oxo-2,6-dimethyl-as-triazin-3-yl;tetrazolo[1,5-b]pyridazin-6-yl; 8-aminotetrazolo[1,5-b]-pyridazin-6-yl;quinol-2-yl; quinol-3-yl; quinol-4-yl; quinol-5-yl; quinol-6-yl;quinol-8-yl; 2-methyl-quinol-4-yl; 6-fluoro-quinol-4-yl;2-methyl,8-fluoro-quinol-4-yl; isoquinol-5-yl; isoquinol-8-yl;isoquinol-1-yl; and quinazolin-4-yl; An alternative group of“heteroaryl” includes: 5-methyl-2-phenyl-2H-pyrazol-3-yl;4-(carboxymethyl)-5-methyl-1,3-thiazol-2-yl; 1,3,4-triazol-5-yl;2-methyl-1,3,4-triazol-5-yl; 1H-tetrazol-5-yl;1-methyl-1H-tetrazol-5-yl;1-(1-(dimethylamino)eth-2-yl)-1H-tetrazol-5-yl;1-(carboxymethyl)-1H-tetrazol-5-yl; 1-(methylsulfonicacid)-1H-tetrazol-5-yl; 1,2,3-triazol-5-yl;1,4,5,6-tetrahydro-5,6-dioxo-4-methyl-as-triazin-3-yl;1,4,5,6-tetrahydro-4-(2-formylmethyl)-5,6-dioxo-as-triazin-3-yl;2,5-dihydro-5-oxo-6-hydroxy-2-methyl-as-triazin-3-yl;2,5-dihydro-5-oxo-6-hydroxy-2-methyl-as-triazin-3-yl;tetrazolo[1,5-b]pyridazin-6-yl; and 8-aminotetrazolo[1,5-b]pyridazin-6-yl.

As used in the specification, the terms “a compound of the presentinvention” and “compounds of the present invention” are intended toinclude the pharmaceutically acceptable salts of compounds having acidicand/or basic moieties.

As used herein, the terms “pharmaceutically acceptable.”“physiologically tolerable” and grammatical variations thereof, as theyrefer to compositions, excipients, carriers, diluents and reagents, areused interchangeably and represent that the materials can be safelyadministered to a subject or patient, especially a human patient.

“Pharmaceutically acceptable salts” are those salts which retain atleast some of the biological activity of the free (non-salt) compoundand which can be administered as drugs or pharmaceuticals to anindividual. Such salts, for example, include: (1) acid addition salts,formed with inorganic acids such as hydrochloric acid, hydrobromic acid,sulfuric acid, nitric acid, phosphoric acid, and the like; or formedwith organic acids such as acetic acid, oxalic acid, propionic acid,succinic acid, maleic acid, tartaric acid and the like; (2) salts formedwhen an acidic proton present in the parent compound either is replacedby a metal ion, e.g., an alkali metal ion, an alkaline earth metal ion,or an aluminum ion; or coordinates with an organic base. Acceptableorganic bases include ethanolamine, diethanolamine, triethanolamine andthe like. Acceptable inorganic bases include aluminum hydroxide, calciumhydroxide, potassium hydroxide, sodium carbonate, sodium hydroxide, andthe like. Further examples of pharmaceutically acceptable salts includethose listed in Berge et al., Pharmaceutical Salts, J. Pharm. Sci. 1977January; 66(1):1-19. Pharmaceutically acceptable salts can be preparedin situ in the manufacturing process, or by separately reacting apurified compound disclosed herein in its free acid or base form with asuitable organic or inorganic base or acid, respectively, and isolatingthe salt thus formed during subsequent purification.

In accordance with the present invention, the compounds and theirpharmaceutically acceptable salts also include the solvent additionforms and/or crystal forms thereof, particularly solvates or polymorphs.Solvates contain either stoichiometric or non-stoichiometric amounts ofa solvent, and are often formed during the process of crystallization.Hydrates are formed when the solvent is water, while alcoholates areformed when the solvent is alcohol. Polymorphs include the differentcrystal packing arrangements of the same elemental composition of acompound. Polymorphs usually have different X-ray diffraction patterns,infrared spectra, melting points, density, hardness, crystal shape,optical and electrical properties, stability, and solubility. Variousfactors such as the recrystallization solvent, rate of crystallization,and storage temperature may cause a single crystal form to dominate.

Unless otherwise specified, the terms “treating,” “treat,” or“treatment” and the like include preventative (e.g., prophylactic) andpalliative treatment. In some embodiments, “treating” does not requireprevention.

As used herein “subject” or “patient” refers to an animal or mammalincluding, but not limited to, human, dog, cat, horse, cow, pig, sheep,goat, chicken, monkey, rabbit, rat, and mouse.

Unless otherwise specified, as used herein, the term “therapeutic”refers to the amelioration of, the prevention of, an improvement of, ora delay in the onset of one or more symptoms of an unwanted condition ordisease of a patient. Embodiments of the present invention are directedto therapeutic treatments by inhibiting TGFβ activity.

The terms “therapeutically effective amount” or “effective amount,” asused herein, means an amount of a compound, or a pharmaceuticallyacceptable salt thereof, often as part of a pharmaceutical composition,sufficient to inhibit, halt, ameliorate, attenuate, delay the onset of,or cause an improvement in one or more symptoms of the disease beingtreated when administered alone or in conjunction with anotherpharmaceutical agent for treatment in a particular subject or subjectpopulation. For example in a human or other mammal, a therapeuticallyeffective amount can be determined experimentally in a laboratory orclinical setting, or may be the amount required by the guidelines of theUnited States Food and Drug Administration, or equivalent foreignagency, for the particular disease and subject being treated.

The term “excipient” means any pharmaceutically acceptable additive,carrier, diluent, adjuvant, or other ingredient, other than the activepharmaceutical ingredient (API), which is typically included in apharmaceutical composition for formulation and/or administration to apatient.

In some embodiments, the salts of the compounds of the invention arepharmaceutically acceptable salts. Where one or more tertiary aminemoiety is present in the compound, the N-oxides are also provided anddescribed. For example, exemplary N-oxide compounds could include:

The invention also intends isotopically-labeled and/orisotopically-enriched forms of compounds described herein. The compoundsherein may contain unnatural proportions of atomic isotopes at one ormore of the atoms that constitute such compounds. In some embodiments,the compound is isotopically-labeled, such as an isotopically-labeledcompound of the formula (I) or variations thereof described herein,where a fraction of one or more atoms are replaced by an isotope of thesame element. Exemplary isotopes that can be incorporated into compoundsof the invention include isotopes of hydrogen, carbon, nitrogen, oxygen,phosphorus, sulfur, chlorine, such as ²H, ³H, ¹¹C, ¹³C, ¹⁴C, ¹³N, ¹⁵O,¹⁷O, ³²P, ³⁵S, ¹⁸F, ³⁶Cl. Certain isotope labeled compounds (e.g. ³H and¹⁴C) are useful in compound or substrate tissue distribution study.Incorporation of heavier isotopes such as deuterium (²H) can affordcertain therapeutic advantages resulting from greater metabolicstability, for example, increased in vivo half-life, or reduced dosagerequirements and, hence may be preferred in some instances.

Isotopically-labeled compounds of the present invention can generally beprepared by standard methods and techniques known to those skilled inthe art or by procedures similar to those described in the accompanyingExamples substituting appropriate isotopically-labeled reagents in placeof the corresponding non-labeled reagent.

The invention also includes any or all metabolites of any of thecompounds described. The metabolites may include any chemical speciesgenerated by a biotransformation of any of the compounds described, suchas intermediates and products of metabolism of the compound.

The compounds of the present invention may also be supplied in the formof a “prodrug” which is designed to release the compound of the presentinvention when administered to a subject. Prodrug designs are well knownin the art, and depend on the substituents contained in any particularcompound of the present invention. For example, a substituent containingsulfhydryl could be coupled to a carrier which renders the compoundbiologically inactive until removed by endogenous enzymes or, forexample, by enzymes targeted to a particular receptor or location in thesubject. Similarly, ester and amide linkages may be employed to maskhydroxyl, amino, or carboxyl groups on an active molecule within thescope of the invention, and such groups may be enzymatically cleaved invivo to release the active molecule.

In particular prodrug embodiments, compounds having a hydroxyl group inthe Ar₂ substituent may be acylated or phosphorylated with groups thatcan be hydrolyzed under physiological conditions at an appreciable rate.Suitable acyl groups may include C1-C8 acyl groups, which may besubstituted, and which can include cyclic and/or aryl groups; forexample, benzoyl, acetyl, formyl, and methoxyacetyl esters of a hydroxylgroup in Ar₂. Similarly, phosphate esters of hydroxyl groups on Ar₂ mayalso be suitable for use as prodrugs, including the mono- and di- andtri-alkyl esters. Any of the phosphate oxygens not alkylated can be OHor OM, where M represents a pharmaceutically acceptable cation.Furthermore, a hydroxyl of Ar₂ can be acylated with the carboxylic acidportion of an amino acid or of a dipeptide formed from two amino acids;such esters are particularly susceptible to in vivo hydrolysis byesterase activity. Accordingly, such esters can often also serve asprodrugs that release the corresponding alcohol in vivo. These compoundsmay also possess intrinsic activity as inhibitors of TGFβ activity;accordingly, they may also be useful as drugs themselves.

Compounds according to the present invention are typically provided in apharmaceutical composition comprising a pharmaceutically acceptablecarrier and/or excipient. A “pharmaceutically acceptable” carrier orexcipient is a material that is not biologically or otherwiseundesirable, e.g., the material may be incorporated into apharmaceutical composition administered to an individual without causingsignificant undesirable biological effects or interacting in adeleterious manner with any of the other components of the composition,wherein it is contained. Pharmaceutically acceptable carriers orexcipients meet the required standards of toxicological andmanufacturing testing and/or are included on the Inactive IngredientGuide prepared by the U.S. Food and Drug administration or an equivalentregulatory agency.

A pharmaceutical composition can comprise one or more compounds of thepresent invention, but in most instances only one compound of thepresent invention is present in a pharmaceutical composition. In someembodiments, a pharmaceutical composition further comprises otherpharmacological active adjuvants, as described below.

Preferably a compound of the present invention selected for use in apharmaceutical composition is bioavailable orally. However, thecompounds of this invention may also be formulated for parenteral (e.g.,intravenous) administration.

A compound of the present invention can be used in the preparation of amedicament by combining the compound or compounds as an activeingredient with a pharmacologically acceptable carrier, which is knownin the art. Depending on the therapeutic form of the medication, thecarrier may be in various forms. In one variation, the manufacture of amedicament is for use in any of the methods disclosed herein.

Methods as provided herein may comprise administering to an individual apharmacological composition that contains an effective amount of acompound of the present invention and a pharmaceutically acceptablecarrier. The effective amount of the compound may in one aspect be adose of between about 0.001-100 mg/kg total body weight, preferably from0.01-50 mg/kg and more preferably about 0.01 mg/kg-10 mg/kg.

The manner of administration and formulation of the compounds of thepresent invention will depend on the nature of the condition, theseverity of the condition, the particular subject to be treated, and thejudgment of the practitioner; formulation will depend on mode ofadministration.

Thus, compounds of the present invention may be formulated for anyavailable delivery route, including an oral, mucosal (e.g., nasal,sublingual, vaginal, buccal or rectal), parenteral (e.g., intramuscular,subcutaneous or intravenous), topical or transdermal. A compound may beformulated with suitable carriers to provide delivery forms thatinclude, but are not limited to, tablets, caplets, capsules (such ashard gelatin capsules or soft elastic gelatin capsules), cachets,troches, lozenges, gums, dispersions, suppositories, ointments,cataplasms (poultices), pastes, powders, dressings, creams, solutions,patches, aerosols (e.g., nasal spray or inhalers), gels, suspensions(e.g., aqueous or non-aqueous liquid suspensions, oil-in-water emulsionsor water-in-oil liquid emulsions), solutions and elixirs.

A compound of the present invention can be used in the preparation of aformulation, such as a pharmaceutical composition, by combining thecompound or compounds as an active ingredient with a pharmaceuticallyacceptable carrier, such as those mentioned above. Depending on thetherapeutic form of the system (e.g., transdermal patch vs. oraltablet), the carrier may be in various forms. In addition,pharmaceutical compositions may contain preservatives, solubilizers,stabilizers, re-wetting agents, emulgators, sweeteners, dyes, adjusters,salts for the adjustment of osmotic pressure, buffers, coating agents orantioxidants. Compositions/formulations comprising the compound may alsocontain other substances which have valuable therapeutic properties.Pharmaceutical compositions may be prepared by known pharmaceuticalmethods. Suitable formulations can be found, e.g., in Remington'sPharmaceutical Sciences, Mack Publishing Company, Philadelphia. Pa.,20^(th) ed. (2000), which is incorporated herein by reference.

A compound of the present invention may be administered to individualsin a form of generally accepted oral compositions, such as tablets,coated tablets, gel capsules in a hard or in soft shell, emulsions orsuspensions. Examples of carriers, which may be used for the preparationof such compositions, are lactose, corn starch or its derivatives, talc,stearate or its salts, etc. Acceptable carriers for gel capsules withsoft shell are, for instance, plant oils, wax, fats, semisolid andliquid poly-ols, and so on. In addition, pharmaceutical formulations maycontain preservatives, solubilizers, stabilizers, re-wetting agents,emulgators, sweeteners, dyes, adjusters, salts for the adjustment ofosmotic pressure, buffers, coating agents or antioxidants.

Compounds of the present invention can be formulated in a tablet in anydosage form described. For example, a compound as described herein or apharmaceutically acceptable salt thereof can be formulated as a 10 mgtablet.

The dose of a compound administered to an individual (such as a human)may vary with the particular compound or salt thereof, the method ofadministration, and the particular stage of disease being treated. Theamount should be sufficient to produce a desirable response, such as atherapeutic or prophylactic response against fibrosis. In someembodiments, the amount of the compound or salt thereof is atherapeutically effective amount. In some embodiments, the amount of thecompound or salt thereof is a prophylactically effective amount. In someembodiments, the amount of compound or salt thereof is below the levelthat induces a toxicological effect (e.g., an effect above a clinicallyacceptable level of toxicity) or is at a level where a potential sideeffect can be controlled or tolerated when the composition isadministered to the individual.

In some embodiments, the amount of compound or salt thereof is an amountsufficient to inhibit a TGFβ kinase, inhibit fibrosis, inhibit cancercell growth and/or proliferation or increase apoptosis of cancer cells.

A compound of the present invention may be administered to an individualin accordance with an effective dosing regimen for a desired period oftime or duration, such as at least about one month, at least about 2months, at least about 3 months, at least about 6 months, or at leastabout 12 months or longer, which in some variations may be for theduration of the individual's life. In one variation, a compound of thepresent invention is administered on a daily or intermittent schedule.The compound can be administered to an individual continuously (forexample, at least once daily) over a period of time. The dosingfrequency can also be less than once daily, e.g., about a once weeklydosing. The dosing frequency can be more than once daily, e.g., twice orthree times daily. The dosing frequency can also be intermittent (e.g.,once daily dosing for 7 days followed by no doses for 7 days, repeatedfor any 14 day time period, such as about 2 months, about 4 months,about 6 months or more). Any of the dosing frequencies can employ any ofthe compounds described herein together with any of the dosagesdescribed herein.

In some embodiments, a pharmaceutical composition is provided as a unitdosage form, such as a tablet, capsule, or individually packagedcontainer (e.g., an ampoule, syringe, or vial).

In some embodiments, the unit dosage form contains a daily dose of acompound of the present invention. In some embodiments, the unit dosageform contains a daily sub-dose of the compound.

In some embodiments, the unit dosage form contains a daily dose of eachof two or more compounds of the present invention. In some embodiments,the unit dosage form contains a daily sub-dose of each of two or morecompounds.

In some embodiments, the unit dosage form contains a daily dose of acompound of the present invention and a daily dose of each of one ormore additional chemotherapeutic agents. In some embodiments, the unitdosage form contains a daily sub-dose of the compound and a dailysub-dose of each of one or more additional chemotherapeutic agents.

In some embodiments, the unit dosage form contains a daily dose of eachof two or more compounds of the present invention and a daily dose ofeach of one or more additional chemotherapeutic agents. In someembodiments, the unit dosage form contains a daily sub-dose of each oftwo or more compounds of the present invention and a daily dose of eachof one or more additional chemotherapeutic agents.

Kits and Articles of Manufacture

This disclosure also provides kits and articles of manufacturecomprising one or more compounds of the present invention or apharmacological composition comprising a compound of the presentinvention or a pharmaceutically acceptable salt thereof. The kits mayemploy any of the compounds disclosed herein. In one variation, the kitemploys a compound described herein or a pharmaceutically acceptablesalt thereof.

Kits generally comprise suitable packaging. The kits may comprise one ormore containers comprising any compound described herein. Each component(if there is more than one component) can be packaged in separatecontainers or some components can be combined in one container wherecross-reactivity and shelf life permit.

The kits may be in unit dosage forms, bulk packages (e.g., multi-dosepackages) or sub-unit doses. For example, kits may be provided thatcontain sufficient dosages of a compound as disclosed herein and/or asecond pharmaceutically active compound useful for a disease detailedherein to provide effective treatment of an individual for an extendedperiod, such as any of a week, 2 weeks, 3 weeks, 4 weeks, 6 weeks, 8weeks, 3 months, 4 months, 5 months, 7 months, 8 months, 9 months, ormore. Kits may also include multiple unit doses of the compounds andinstructions for use and be packaged in quantities sufficient forstorage and use in pharmacies (e.g., hospital pharmacies and compoundingpharmacies).

The kits may optionally include a set of instructions, generally writteninstructions, although electronic storage media (e.g., magnetic disketteor optical disk) containing instructions are also acceptable, relatingto the use of component(s) of the disclosed methods. The instructionsincluded with the kit generally include information as to the componentsand their administration to an individual.

Therapeutic Uses

Compounds of the present invention can be used to treat disorders andconditions associated with fibroproliferation, particularly conditionscharacterized by excessive activity of TGFβ. A “fibroproliferationdisorder” includes fibroproliferative diseases that affect many tissuesand organ systems. Diseases in which fibrosis is a major cause ofmorbidity and mortality include the interstitial lung diseases,osteoporosis, myelofibrosis (also known as myeloid metaplasia), livercirrhosis, liver fibrosis resulting from chronic hepatitis B or Cinfection, kidney disease, heart disease especially cardiac fibrosisoccurring after infarction and progressive heart failure and inhypertensive vasculopathy, and systemic sclerosis. Fibroproliferativedisorders also include nasal polyposis, systemic and local scleroderma,keloids and hypertrophic scars, atherosclerosis, restenosis, and eyediseases including macular degeneration and retinal and vitrealretinopathy. Additional fibrotic disorders include keloid formation,excessive scarring occurring during the healing of wounds includingsurgical wounds and traumatic lacerations, chemotherapeutic drug-inducedfibrosis, radiation-induced fibrosis, and injuries and burns Fibrotictissue remodeling can also influence cancer metastasis and acceleratechronic graft rejection in transplant recipients.

Specific diseases benefited by TGFβ inhibition thus includecardiovascular diseases such as congestive heart failure, dilatedcardiomyopathy, myocarditis, or vascular stenosis associated withatherosclerosis, angioplasty treatment, or surgical incisions ormechanical trauma; kidney diseases associated with fibrosis and/orsclerosis, including glomerulonephritis of all etiologies, diabeticnephropathy, and all causes of renal interstitial fibrosis, includinghypertension, complications of drug exposure, such as cyclosporin.HIV-associated nephropathy, transplant nephropathy, chronic ureteralobstruction; hepatic diseases associated with excessive scarring andprogressive sclerosis, including cirrhosis due to all etiologies,disorders of the biliary tree, and hepatic dysfunction attributable toinfections such as hepatitis virus or parasites; syndromes associatedwith pulmonary fibrosis with consequential loss of gas exchange orability to efficiently move air into and out of the lungs, includingadult respiratory distress syndrome, idiopathic pulmonary fibrosis, orpulmonary fibrosis due to infectious or toxic agents such as smoke,chemicals, allergens, or autoimmune disease; all collagen vasculardisorders of a chronic or persistent nature including progressivesystemic sclerosis, polymyositis, scleroderma, dermatomyositis,fascists, or Raynaud's syndrome, or arthritic conditions such asrheumatoid arthritis; eye diseases associated with fibroproliferativestates, including proliferative vitreoretinopathy of any etiology orfibrosis associated with ocular surgery such as retinal reattachment,cataract extraction, or drainage procedures of any kind; excessive orhypertrophic scar formation in the dermis occurring during wound healingresulting from trauma or surgical wounds; disorders of thegastrointestinal tract associated with chronic inflammation, such asCrohn's disease or ulcerative colitis or adhesion formation as a resultof trauma or surgical wounds, polyposis or states post polyp surgery;chronic scarring of the peritoneum associated with endometriosis,ovarian disease, peritoneal dialysis, or surgical wounds; neurologicalconditions characterized by TGFβ production or enhanced sensitivity toTGFβ, including conditions post-traumatic or hypoxic injury, Alzheimer'sdisease, and Parkinson's disease; diseases of the joints involvingscarring sufficient to impede mobility or produce pain, includingconditions post-mechanical or surgical trauma, osteoarthritis andrheumatoid arthritis; and cancer, including lung cancer, skin cancer,colorectal cancer and cancers of the breast, pancreas, and brain,including glioma.

The modulation of the immune and inflammation systems by TGFβ (Wahl etal., Immunol. Today (1989) 10:258-61) includes stimulation of leukocyterecruitment, cytokine production, and lymphocyte effector function, andinhibition of T-cell subset proliferation, B-cell proliferation,antibody formation, and monocytic respiratory burst. TGFβ is astimulator for the excess production of extracellular matrix proteins,including fibronectin and collagen. It also inhibits the production ofenzymes that degrade these matrix proteins. The net effect is theaccumulation of fibrous tissue which is the hallmark offibroproliferative diseases.

In one aspect, the invention provides a method of inhibiting a TGFβ3receptor kinase receptor, comprising administering to an individual aneffective amount of one or more compounds of the invention, or a saltthereof (e.g., a pharmaceutically acceptable salt). In one aspect of themethod, a compound of the invention or salt thereof inhibits binding ofa ligand to the TGFβ receptor and/or reduces or eliminates or increasesor enhances or mimics an activity of the TGFβ receptor in a reversibleor irreversible manner. In some aspects, a compound of the inventioninhibits binding of a ligand to the TGFβ3 receptor by at least about orby about any one of 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95% or100% as determined by an assay described herein. In some aspects, acompound of the invention reduces an activity of the TGFβ receptor by atleast about or about any of 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%,95% or 100% as compared to the corresponding activity in the samesubject prior to treatment with the receptor modulator or compared tothe corresponding activity in other subjects not receiving the compound.In one aspect, the individual has or is believed to have a disorder inwhich the TGFβ receptor is implicated. In certain variations, a compoundor composition of the invention is used to treat or prevent a TGFβreceptor related disorder, such as cancer (e.g., neuroblastoma,pancreatic cancer and colon cancer). In one aspect, the method comprisesadministering to the individual a compound provided herein, or apharmaceutically acceptable salt thereof, including but not limited to acompound of the invention such as a compound according to any one ormore of formulae I. (A) to (D); (Aa) to (Af); (Aa-1) to (Aa-9); (Aa-1a)to (Aa-1g); (Ab-1) to (Af-1); (Ba) to (Bf); (Ba-1) to (Bf-1); or acompound of Tables 3 or 4, or an isomer thereof, or a salt (such as apharmaceutically acceptable salt) of any of the foregoing. In oneaspect, the individual is a human in need of cancer treatment.

In some embodiments, the amount of the compound or pharmaceuticallyacceptable salt thereof that is administered to an individual is anamount sufficient to decrease the size of a tumor, decrease the numberof cancer cells, or decrease the growth rate of a tumor by at leastabout any of 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95% or 100%compared to the corresponding tumor size, number of cancer cells, ortumor growth rate in the same subject prior to treatment or compared tothe corresponding activity in other subjects not receiving thetreatment. Standard methods can be used to measure the magnitude of thiseffect, such as in vitro assays with purified enzyme, cell-based assays,animal models, or human testing.

Examples of in vitro and cell-based assays are provided in the Examples,below. A variety of appropriate and accepted animal models are wellknown in the art and include, for example, bleomycin-induced pulmonaryfibrosis models (e.g., Peng et al., PLoS ONE 8(4), e59348, 2013; Izbickiet al., Int. J. Exp. Path. 83, 111-19, 2002); colorectal cancer models(e.g., Zigmond et al., PLoS ONE 6(12), e28858, 2011); and bonemetastasis models (e.g., Mohammad et al., Cancer Res. 71, 175-84, 2011;Buijs et al., BoneKEy Reports 1, Article number: 96, 2012).

In some embodiments, the cancer that may be treated is a solid tumorsuch as sarcomas and carcinomas. In some embodiments, the cancer thatmay be treated is a liquid tumor such as leukemia. Examples of cancersthat may be treated by methods of the invention include, but are notlimited to, breast cancer, prostate cancer, ovarian cancer, lung cancer,colon cancer, brain tumors, gastric cancer, liver cancer, thyroidcancer, endometrial cancer, gallbladder cancer, kidney cancer,adrenocortical cancer, sarcoma, skin cancer, head and neck cancer,leukemia, bladder cancer, colorectal cancer, hematopoietic cancer andpancreatic cancer. In some embodiments, the breast cancer is breastcarcinoma (ER negative or ER positive), primary breast ductal carcinoma,mammary adenocarcinoma, mammary ductal carcinoma (ER positive, ERnegative or HER2 positive), HER2 positive breast cancer, luminal breastcancer or triple negative breast cancer (TNBC). In some embodiments, thebreast cancer is unclassified. In some embodiments, the triple negativebreast cancer is a basal-like TNBC, a mesenchymal TNBC (mesenchymal ormesenchymal stem-like), an immunomodulatory TNBC, or a luminal androgenreceptor TNBC. In some embodiments, the prostate cancer is prostateadenocarcinoma. In some embodiments, the ovarian cancer is ovaryadenocarcinoma. In some embodiments, the lung cancer is lung carcinoma,non-small lung carcinoma, adenocarcinoma, mucoepidermoid, anaplastic,large cell, or unclassified. In some embodiments, the colon cancer iscolon adenocarcinoma, colon adenocarcinoma from a metastatic site lymphnode, metastatic colorectal cancer, or colon carcinoma. In someembodiments, a brain tumor is glioblastoma, astrocytoma, meduloblastoma,meningioma or neuroblastoma. In some embodiments, gastric cancer isstomach cancer. In some embodiments, liver cancer is hepatocellularcarcinoma, hepatoblastoma or cholangiocarcinoma. In some embodiments,liver cancer is hepatitis B virus derived. In some embodiments, livercancer is virus negative. In some embodiments, thyroid cancer ispapillary thyroid carcinoma, follicular thyroid cancer or medullarythyroid cancer. In some embodiments, endometrial cancer is high gradeendometroid cancer, uterine papillary serous carcinoma or uterine clearcell carcinoma. In some embodiments, gallbladder cancer is gallbladderadenocarcinoma or squamous cell gallbladder carcinoma. In someembodiments, kidney cancer is renal cell carcinoma or urothelial cellcarcinoma. In some embodiments, adrenocortical cancer is adrenalcortical carcinoma. In some embodiments, sarcoma is synovial sarcoma,osteosarcoma, rhabdomiosarcoma, fibrosarcoma or Ewing's sarcoma. In someembodiments, skin cancer is basal cell carcinoma, squamous carcinoma ormelanoma. In some embodiments, head and neck cancer is oropharyngealcancer, nasopharyngeal cancer, laryngeal cancer and cancer of thetrachea. In some embodiments, the leukemia is acute promyelocyticleukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia,chronic myelogenous leukemia, mantle cell lymphoma or multiple myeloma.In some embodiments, the leukemia is acute promyelocytic leukemia, acutelymphoblastic leukemia, chronic lymphocytic leukemia, chronicmyelogenous leukemia, mantle cell lymphoma or multiple myeloma.

The invention additionally provides a method for treating a tumorcomprising contacting the tumor with an effective amount of one or morecompounds of the invention, or a salt thereof. In one aspect of themethod, a compound or salt thereof is administered to an individual inneed of tumor treatment. Exemplary tumors are derived from carcinomas ofthe breast, prostate, ovary, lung, or colon. In one aspect, thetreatment results in a reduction of the tumor size. In another aspect,the treatment slows or prevents tumor growth and/or metastasis.

The invention further provides methods for treating a hematopoieticmalignancy comprising administering an effective amount of one or morecompounds of the invention to an individual in need thereof. In someembodiments, the hematopoietic malignancy is acute promyelocyticleukemia.

Any of the methods of treatment provided herein may be used to treat aprimary tumor. Any of the methods of treatment provided herein may alsobe used to treat a metastatic cancer (that is, cancer that hasmetastasized from the primary tumor). Any of the methods of treatmentprovided herein may be used to treat cancer at an advanced stage. Any ofthe methods of treatment provided herein may be used to treat cancer ata locally advanced stage. Any of the methods of treatment providedherein may be used to treat early stage cancer. Any of the methods oftreatment provided herein may be used to treat cancer in remission. Insome of the embodiments of any of the methods of treatment providedherein, the cancer has reoccurred after remission. In some embodimentsof any of the methods of treatment provided herein, the cancer isprogressive cancer.

Any of the methods of treatment provided herein may be used to treat anindividual (e.g., human) who has been diagnosed with or is suspected ofhaving cancer. In some embodiments, the individual may be a human whoexhibits one or more symptoms associated with cancer. In someembodiments, the individual may have advanced disease or a lesser extentof disease, such as low tumor burden. In some embodiments, theindividual is at an early stage of a cancer. In some embodiments, theindividual is at an advanced stage of cancer. In some of the embodimentsof any of the methods of treatment provided herein, the individual maybe a human who is genetically or otherwise predisposed (e.g., has one ormore so-called risk factors) to developing cancer who has or has notbeen diagnosed with cancer. In some embodiments, these risk factorsinclude, but are not limited to, age, sex, race, diet, history ofprevious disease, presence of precursor disease, genetic (e.g.,hereditary) considerations, and environmental exposure. In someembodiments, the individuals at risk for cancer include, e.g., thosehaving relatives who have experienced this disease and those whose riskis determined by analysis of genetic or biochemical markers. In someembodiments, the individual does not have type I diabetes. In someembodiments, the individual does not have type II diabetes withsustained hyperglycemia or type II diabetes with hyperglycemia forprolonged duration (e.g., for several years).

Any of the methods of treatment provided herein may be practiced in anadjuvant setting. In some embodiments, any of the methods of treatmentprovided herein may be used to treat an individual who has previouslybeen treated for cancer, e.g., with one or more other therapies such asradiation, surgery or chemotherapy. Any of the methods of treatmentprovided herein may be used to treat an individual who has notpreviously been treated for cancer. Any of the methods of treatmentprovided herein may be used to treat an individual at risk fordeveloping cancer, but who has not been diagnosed with cancer. Any ofthe methods of treatment provided herein may be used as a first linetherapy. Any of the methods of treatment provided herein may be used asa second line therapy.

Any of the methods of treatment provided herein in one aspect reduce theseverity of one or more symptoms associated with cancer by at leastabout any of 10%, 20%, 30%, 40%, 50% 60%, 70%, 80%, 90%, 95% or 100%compared to the corresponding symptom in the same subject prior totreatment or compared to the corresponding symptom in other subjects notreceiving a compound or composition of the invention.

Any of the methods of treatment provided herein may be used to treat,stabilize, prevent, and/or delay any type or stage of cancer. In someembodiments, the individual is at least about any of 40, 45, 50, 55, 60,65, 70, 75, 80, or 85 years old. In some embodiments, one or moresymptoms of the cancer are ameliorated or eliminated. In someembodiments, the size of a tumor, the number of cancer cells, or thegrowth rate of a tumor decreases by at least about any of 10%, 20%, 30%,40%, 50%, 60%, 70%, 80%, 90%, 95% or 100%. In some embodiments, thecancer is delayed or prevented.

In some embodiments, a compound or composition of the invention may beused to treat or prevent cancer in conjunction with a second therapyuseful to reduce one or more side effects associated with administeringthe compound or composition of the invention. In some embodiments, thesecond compound for such combination therapy is selected from agentsused for the treatment of glucose-related disorders such as Type 2diabetes mellitus, impaired glucose tolerance, Insulin ResistanceSyndrome and hyperglycemia. Examples of such agents include oralantidiabetic compounds from the classes of sulfonylureas, biguanides,thiazolidinediones, alpha-glucosidase inhibitors, meglitinides, otherinsulin-sensitizing compounds and/or other antidiabetic agents.Particular examples comprise Metformin (N,N-dimethylimidodicarbonimidicdiamide), sulfonylureas and the like, or a salt of the foregoing.Testing of glucose concentration levels in an individual receiving acompound of the present invention may be followed by theco-administration of such a second agent (e.g., Metformin) as part of acombination therapy where appropriate (e.g., where the results of aglucose concentration level test in an individual indicate that suchcombination therapy will be or is expected to be beneficial for theindividual).

In some embodiments, the compounds and compositions of the invention maybe used to treat or prevent cancer in conjunction with a second therapyuseful for cancer treatment. The second therapy includes, but is notlimited to, surgery, radiation, and/or chemotherapy.

Use of Compounds of the Invention in Combination with CancerImmunotherapies

In some embodiments, a compound of the invention is administered to apatient in combination with one or more cancer immunotherapies,including cell-based therapies (“cancer vaccines”), antibody therapies,cytokine therapies, and other immunosuppressive mediators such asindoleamine 2,3-dioxygenase (IDO). Unless otherwise indicated, “incombination” as used herein includes substantially simultaneousadministration of the compound of the invention and one or more cancerimmunotherapies (either in the same composition or in separatecompositions) as well as sequential administration.

Cell-based therapies include, but are not limited to, natural killercells, lymphokine-activated killer cells, cytotoxic T cells, regulatoryT cells, and dendritic cells. In some embodiments, a compound of theinvention is used in combination with sipuleucel-T (e.g., PROVENGE®), totreat prostate cancer. In some embodiments, adjuvants, such as GM-CSF,are used to attract and/or activate dendritic cells.

Antibody therapies include, but are not limited to, antibodies to cellsurface receptors, such as epidermal growth factor receptor and HER2, aswell as antibodies which block immune checkpoints (e.g., antibodieswhich bind to molecules such as PD-1, PD-L1, and CTLA-4). The term“antibody” as used herein includes monoclonal antibodies, humanized orchimeric antibodies, bispecific antibodies (e.g., BiTE), single chainantibodies, and binding fragments such as Fab, Fab′ F(ab′)₂, Fabc, andFv. Antibodies may be used alone or may be conjugated, for example, to amoiety which is either toxic to cells (antibody drug conjugate, or ADC)or is radioactive. Examples of antibody therapies include Pidilizumab,Alemtuzumab, Bevacizumab, Brentuximab vedotin, Cetuximab, Gemtuzumabozogamicin, Ibritumomab tiuxetan, Ipilimumab, Ofatumumab, Panitumumab,Rituximab, Tositumomab, and Trastuzumab.

Cytokine therapies include, but are not limited to, GM-CSF, interleukins(e.g., IL-2, IL-7, IL-10, IL-12, IL-15, IL-18, IL-21), and interferons(e.g., interferon α).

Examples of compounds of formula (I) are shown in Table 3 and Table 4.Specific synthetic methods for preparing the compounds of Table 3 areprovided in the following examples.

In one embodiment, the invention relates to Compounds presented inTables 3 and 4, and uses thereof, other than Compound Nos. C-E 1, C-E 1aand C-E 1b.

In another embodiment, the invention relates to Compound Nos. 1, 1a, 1b,2, 2a, 2b, 3, 3a, 3b, 4, 4a, 4b, 5, 5a, 5b, 6, 6a, 6b, 7, 7a, 7b, 8, 9,10, 10a, 10b, 11, 1a, 11b, 12, 12a, 12b, 13, 13a, 13b, 14, 15, 16, 16a,16b, 17, 17a, 17b, 18, 19, 20, 20a, 20b, 21, 21a, 21b, 22, 23, 23a, 23b,24, 24a, 24b, 25, 25a, 25b, 26, 27, 28, 28a, 28b, 29, 30, 31, 31a, 31b,32, 33, 34, 35, 36, 37, 37a, 37b, 38, 38a, 38b, 39, 39a, 39b, 40, 40a,40b, 41, 42, 43, 43a, 43b, 44, 44a, 44b, 45, 46, 46a, 46b, 47, 47a, 47b,48, 49, 50, 51, 51a, 51b, 52, 52a, 52b, 53, 53a, 53b, and 54, and usesthereof.

In another embodiment, the invention relates to Compound Nos. 2.1, 2.1a,2.1b, 2.2, 2.2a, 2.2b, 2.3, 2.3a, 2.3b, 2.4, 2.4a, 2.4b, 2.5, 2.6, 2.6a,2.6b, 2.7, 2.7a, 2.7b, 2.8, 2.8a, 2.8b, 2.9, 2.9a, 2.9b, 2.10, 2.10a,2.10b, 2.11, 2.11a, 2.11b, 2.12, 2.12a, 2.12b, 2.13, 2.13a, 2.13b, 2.14,2.14a, 2.14b, 2.15, 2.15a, 2.15b, 2.16, 2.16a, 2.16b, 2.17, 2.17a,2.17b, 2.18, 2.18a, 2.18b, 2.19, 2.19a, 2.19b, 2.20, 2.20a, 2.20b, 2.21,2.21a, 2.21b, 2.22, 2.22a, 2.22b, 2.23, 2.23a, 2.23b, 2.24, 2.24a,2.24b, 2.25, 2.26, 2.27, 2.28, 2.29, 2.29a, 2.29b, 2.30, 2.30a, 2.30b,2.31, 2.31a, 2.31b, 2.32, 2.32a, 2.32b, 2.33, 2.34, 2.35, 2.36, 2.37,2.38, 2.38a, 2.38b, 2.39, 2.40, 2.41, 2.41a, 2.41b, 2.42, 2.42a, 2.42b,2.43, 2.44, 2.45, 2.46, 2.47, and 2.48, and uses thereof.

TABLE 3

C-E 1

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

31

32

33

34

35

36

37

38

39

40

41

42

43

44

45

46

47

48

49

50

51

52

53

54

Those entries with additional a and b entries are intended to designatethe stereoisomers of the illustrated structure. It is understood thatsuch stereoisomers may be resolved into the respective enantiomers. Thecompounds of the invention include the enantiomers in its isomericallypure form or in a composition comprising mixtures of compounds of theinvention in any ratio including two stereochemical forms, such as in aracemic or non-racemic mixture. Individual enantiomers can be prepared,for example, by either chiral separation of racemic mixtures usingtechniques known to those skilled in the art, or by employing chirallypure enantiomeric reagents during the synthetic process. As an example,racemic compound 1, bearing one chiral center, can be resolved into itsindividual enantiomers 1a and 1b.

The compounds illustrated in Table 4 can be prepared in a manneranalogous to the techniques used in connection with the preparation ofthe Table 3 compounds and in accordance, using appropriate, analogousstarting materials and by utilizing the general synthetic schemesillustrated below.

TABLE 4

2.1

2.2

2.3

2.4

2.5

2.6

2.7

2.8

2.9

2.10

2.11

2.12

2.13

2.14

2.15

2.16

2.17

2.18

2.19

2.20

2.21

2.22

2.23

2.24

2.25

2.26

2.27

2.28

2.29

2.30

2.31

2.32

2.33

2.34

2.35

2.36

2.37

2.38

2.39

2.40

2.41

2.42

2.43

2.44

2.45

2.46

2.47

2.48General Synthetic Methods

A number of synthetic routes may be employed to produce compounds of thepresent invention. In general, the compounds may be synthesized fromconventional starting materials using reactions known in the art. Inparticular, compounds may be prepared by a number of processes asgenerally described below in the General Synthetic Schemes and morespecifically in the Examples hereinafter. In the following processdescriptions, the symbols when used in the formulae depicted are to beunderstood to represent those groups described above in relation to theformulae herein.

Chromatography, recrystallization and other conventional separationprocedures may also be used with intermediates or final products whereit is desired to obtain a particular isomer of a compound or tootherwise purify a product of a reaction.

The following abbreviations are used herein: thin layer chromatography(TLC); hour (h); minute (min); second (sec); ethanol (EtOH);dimethylsulfoxide (DMSO); N,N-dimethylformamide (DMF); trifluoroaceticacid (TFA); tetrahydrofuran (THF); Normal (N); aqueous (aq.); methanol(MeOH); dichloromethane (DCM); ethyl acetate (EtOAc); Retention factor(Rf); room temperature (RT); acetyl (Ac);4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene (Xantphos);1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxid hexafluorophosphate (HATU); N,N-diisopropylamine (DIPEA); methyl(Me); ethyl (Et); phenyl (Ph); para-toluenesulfonic acid (PTSA);Diisobutylaluminium hydride (DiBAL-H); Diphenyl phosphoryl azide (DPPA);Tetrakis(triphenylphosphine)palladium(0) (Pd[P(C₆H₅)₃]₄, and (tetrakis);meta-Chloroperoxybenzoic acid (m-CPBA),2,2′-Bis(diphenylphosphino)-1,1′-binaphthyl (BINAP).

The following General Synthetic Schemes and Examples are provided toillustrate but not to limit the invention. Those skilled in the art willbe familiar with many of the reaction steps described. Particularpublications are presented to assist with the understanding of certainsteps of the synthetic route. In some of the reaction schemes thatfollow a terminal methyl (CH₃) and a terminal methylene (═CH₂) are shownwithout the providing the text for these groups (due to spacelimitations), as is a common convention and well understood by thoseskilled in the chemical arts.

In General Synthetic Scheme 1, one route to compounds of formula (I)commences with a di-halo substituted pyridine that is furtherfunctionalized with iodine, under base-mediated iodination conditions,in step 1. The iodo group is selectively substituted underpalladium-mediated amination conditions with amines, such as the methyl4-aminonicotinate shown here, in step 2 to give the 4-aminointermediate. Separately, in step 3, appropriately functionalizedaromatic, or heteroaromatic, rings can be treated under base-mediatedboronation conditions to provide the boronic acid intermediate which,when applied to the Suzuki coupling conditions of step 4, provide theregioselectively coupled product. Basic hydrolysis conditions of step 5,convert the ester group to its acid which, when subjected to aminecoupling conditions of step 6 in the presence of various aminesincluding chiral amines, such as (S)-1-aminopropan-2-ol shown, yieldsthe final desired product. Each step presented in General SyntheticScheme 1 is amenable to a variety of appropriately functionalizedreagents as appropriate to the embodiments provided herein, and will befamiliar to those skilled in the art.

General Synthetic Scheme 2 presents a route to analogs of the productsof step 4 in General Synthetic Scheme 1, wherein the substituent A offormula (I) can now be for example a prop-2-enyl or an isopropyl group.Step 1 commences with treatment of an appropriately functionalizedaromatic or heteroaromatic ring bearing an ester, with a Grignardreagent such as methylmagnesium bromide, and results in the additionproduct—a tertiary alcohol. Regioselective coupling in step 2 underpalladium-mediated conditions with various boronic acids, similar tothose in step 4 of General Synthetic Scheme 1, provides the coupledproduct. Acid based dehydration conditions of step 3 results in thealkene intermediate which can be subjected to amine coupling conditionsof step 4 to provide the 4-aminopyridyl product. If necessary, thepropene group can be reduced under hydrogenation conditions of step 5 toyield the propyl substituted derivative. The products of steps 4 and 5can be utilized as described above in steps 5 and 6 of General SyntheticScheme 1.

General Synthetic Scheme 3 presents a route to other analogs of theproducts of step 1 in General Synthetic Scheme 1, wherein thesubstituent A of formula (I) can now be for example a vinyl group. Step1 commences with reduction of an appropriately functionalized aromaticor heteroaromatic ring bearing an ester, to afford the primary alcoholwhich, when subjected to Swern oxidation conditions of step 2, yieldsthe aldehyde. Subjecting the aldehyde to various Grignard reagents instep 3, such as methylmagnesium bromide, provides the secondary alcoholwhich can undergo regioselective coupling in step 4 with various boronicacids as described in the previous General Synthetic Schemes, to providethe coupled product. The alcohol group can be dehydrated in step 5 undersimilar conditions as presented in step 3 of General Synthetic Scheme 2,to yield the vinyl product. This product can be utilized as described instep 2 of General Synthetic Scheme 1.

General Synthetic Scheme 4 also presents a route to other analogs of theproducts of step 1 in General Synthetic Scheme 1, wherein thesubstituent A of formula (I) can now be for example a methoxy group.This route commences with protection of the alcohol group attached to anappropriately functionalized aromatic or heteroaromatic ring, in theexample provided in step 1 to give the methoxymethoxy (“MOM”)derivative. Base-mediated iodination conditions of step 2 yield theregioisomeric iodo intermediate, which can be treated to acid hydrolysisconditions of step 3 to deprotect the alcohol group, and finally in step4, alkylation with various alkyl iodides such as methyl iodide, resultsin the methoxy substituted product. This product can be utilized asdescribed in step 2 of General Synthetic Scheme 1.

General Synthetic Scheme 5 also presents a route to other analogs of theproducts of step 1 in General Synthetic Scheme 1, wherein thesubstituent A of formula (I) can now be for example an amino group. Step1 presents the hydrolysis of an appropriately functionalized methylnicotinate ester to its acid derivative, followed in step 2 by a Curtiusrearrangement to provide the Boc-protected amine group. Deprotection ofthe amine under mild acidic conditions of step 3 provides the free aminewhich, in step 4, can be alkylated with various alkyl halides such asmethyl iodide to give the dimethylamino product. Regioselective couplingunder Suzuki conditions with various boronic acids presented in step 5provides an appropriate intermediate that can be utilized in step 2 ofGeneral Synthetic Scheme 1.

It is understood that General Synthetic Schemes 1 to 5 present syntheticroutes involving steps clearly familiar to those skilled in the art,wherein the substituents described in compounds of formula (I) hereincan be varied with a choice of appropriate starting materials andreagents utilized in the steps presented.

EXAMPLES Comparative Example 1 Synthesis of4-[[6-(5-chloro-2-fluoro-phenyl)-3-isopropyl-2-pyridyl]amino]-N-(2-hydroxypropyl)pyridine-3-carboxamide

Step 1: Synthesis of 2-(6-bromo-3-pyridyl)propan-2-ol

To a stirred solution of 2,5-dibromopyridine (20 g, 84.4 mmol) indiethyl ether (300 mL) was added a 2.5M solution of n-BuLi in hexane(8.8 mL, 22.16 mmol) at −78° C. and the reaction mixture was stirred atthe same temperature for 1 h. To this stirred reaction mixture was addedacetone (8 mL, 109.7 mmol) dropwise and the reaction mixture was stirredat −78° C. for 45 min. The progress of reaction was monitored by TLC.After completion of reaction, the mixture was quenched with an aqueoussolution of ammonium chloride (100 mL) and extracted by adding morediethyl ether (1000 mL). The organic layer was dried over sodiumsulfate, and concentrated under reduced pressure to give a crudeproduct. The crude product was purified by column chromatography onsilica gel (100-200 mesh) using 8% EtOAc-hexane system as eluent toafford 2-(6-bromo-3-pyridyl)propan-2-ol (9.9 g).

Step 2: Synthesis of (5-chloro-2-fluoro-phenyl)boronic acid

To a solution of 2-bromo-4-chloro-1-fluoro-benzene (5 g, 0.0238 mol) inanhydrous diethyl ether (30 mL) was added a 2M solution of n-BuLi inn-hexane (13 mL, 0.0262 mol) at −70° C. under nitrogen atmosphere. Thereaction mixture was stirred at the same temperature for 30 min. Then,to this reaction mixture was added triisopropyl borate (4.93 g, 0.0262mol) dropwise. The reaction mixture turned into a white slurry, whichwas further stirred at −70° C. for 30 min and then warmed to RT andstirred for 1 h. The progress of reaction was monitored by TLC and 1HNMR. After completion of the reaction, the mixture was hydrolyzed with 6N HCl, stirred for 1 h and the product was extracted with EtOAc (50 mL).The organic layer was washed with brine and concentrated under reducedpressure to obtain a sticky compound which was triturated with n-pentaneto afford (5-chloro-2-fluoro-phenyl)boronic acid (2.2 g) as an off whitesolid.

Step 3: Synthesis of2-[6-(5-chloro-2-fluoro-phenyl)-3-pyridyl]propan-2-ol

To a solution 2-(6-bromo-3-pyridyl)propan-2-ol (1.5 g, 6.94 mmol) and(5-chloro-2-fluoro-phenyl)boronic acid (1.81 g, 10.41 mmol) in DMF (20mL) and water (20 mL) was added NaHCO₃ (1.16 g, 0.013 mmol). Thereaction mixture was purged with nitrogen for 30 min. To this reactionmixture was added tetrakis(triphenylphosphine)palladium(0) (401 mg,0.347 mmol) and then the reaction mixture was heated at 100° C.overnight. The progress of reaction was monitored by LCMS. Aftercompletion of the reaction, to the reaction mixture was added water (75mL) and the product was extracted with EtOAc (2×250 mL). The combinedorganic layer was washed with water (4×100 mL), dried over sodiumsulfate and concentrated under reduced pressure to give a crude product.The crude product was purified by column chromatography on silica gel(100-200 mesh) using 20-60% EtOAc-hexane to afford2-[6-(5-chloro-2-fluoro-phenyl)-3-pyridyl]propan-2-ol (1.1 g).

Step 4: Synthesis of2-[6-(5-chloro-2-fluoro-phenyl)-3-pyridyl]propan-2-ol

To a stirred solution of2-[6-(5-chloro-2-fluoro-phenyl)-3-pyridyl]propan-2-ol (2 g, 7.54 mmol)in DCM (12 mL) was added mCPBA (1.95 g, 11.32 mmol) in portions at 0° C.The reaction mixture was stirred at RT overnight. The progress ofreaction was monitored by TLC and LCMS. After completion of thereaction, the DCM layer was washed with 1 N HCl (2×100 mL). The aqueouslayer was then concentrated under reduced pressure to give N-oxide of2-[6-(5-chloro-2-fluoro-phenyl)-3-pyridyl]propan-2-ol as HCl salt (1.9g) as an off white solid.

Step 5: Synthesis of2-chloro-6-(5-chloro-2-fluoro-phenyl)-3-isopropenyl-pyridine

A mixture of the N-oxide of2-[6-(5-chloro-2-fluoro-phenyl)-3-pyridyl]propan-2-ol (1.9 g, 6.76 mmol)and POCl₃ (9.7 mL, 101.4 mmol) was heated to reflux at 80° C. for 2 h.The progress of reaction was monitored by LCMS. After completion of thereaction, the POCl₃ was evaporated under reduced pressure. An aqueoussolution of NaHCO₃ was added to the residue, and the product wasextracted with EtOAc (2×250 mL). The combined organic layer was driedover sodium sulfate and concentrated under reduced pressure to give apale yellow liquid compound that was purified by column chromatographyon silica gel (100-200 mesh) using 0.5% EtOAc-hexane system as eluent toafford 2-chloro-6-(5-chloro-2-fluoro-phenyl)-3-isopropenyl-pyridine (600mg) as a yellow oily liquid.

Step 6: Synthesis of2-chloro-6-(5-chloro-2-fluoro-phenyl)-3-isopropyl-pyridine

To a stirred solution of2-chloro-6-(5-chloro-2-fluoro-phenyl)-3-isopropenyl-pyridine (600 mg,2.13 mmol) in ethanol (5 mL) was added PtO₂ (100 mg). The reactionmixture was hydrogenated using hydrogen bladder for 4 h. The progress ofreaction was monitored by NMR After completion of the reaction, themixture was filtered through a celite bed and the celite bed washed withMeOH (200 mL). The filtrate was concentrated under reduced pressure toobtain 2-chloro-6-(5-chloro-2-fluoro-phenyl)-3-isopropyl-pyridine (570mg) as a pale yellow liquid.

Step 7: Synthesis of4-[[6-(5-chloro-2-fluoro-phenyl)-3-isopropyl-2-pyridyl]amino]pyridine-3-carboxylateacid

To a solution of2-chloro-6-(5-chloro-2-fluoro-phenyl)-3-isopropyl-pyridine (570 mg, 2.01mmol) and methyl 4-aminopyridine-3-carboxylate (306 mg, 2.01 mmol) indioxane (3 mL) was added Cs₂CO₃ (918 mg, 2.8 mmol). The reaction mixturewas purged with nitrogen for 1 h. Then, to this reaction mixture wasadded BINAP (175 mg, 0.281 mmol) and Pd(OAc)₂. The reaction mixture washeated at 90° C. overnight. The progress of reaction was monitored byLCMS and TLC. After completion of the reaction, the product wasextracted with EtOAc (2×200 mL). The combined organic layer wasconcentrated under reduced pressure to give a crude product. The crudeproduct was purified by column chromatography on silica gel (100-200mesh) using 20% EtOAc-hexane system as eluent to afford methyl4-[[6-(5-chloro-2-fluoro-phenyl)-3-isopropyl-2-pyridyl]amino]pyridine-3-carboxylateacid (360 mg) as a white solid compound.

Step 8: Synthesis of4-[[6-(5-chloro-2-fluoro-phenyl)-3-isopropyl-2-pyridyl]amino]pyridine-3-carboxylicacid

To a solution of methyl4-[[6-(5-chloro-2-fluoro-phenyl)-3-isopropyl-2-pyridyl]amino]pyridine-3-carboxylate(360 mg, 0.90 mmol) in MeOH (6 mL) was added sodium hydroxide (72 mg,1.30 mmol) in water (1 mL). The reaction mixture was heated at refluxfor 1 h. The progress of reaction was monitored by TLC and NMR. Aftercompletion of the reaction, the mixture was concentrated and toluene wasadded to give4-[[6-(5-chloro-2-fluoro-phenyl)-3-isopropyl-2-pyridyl]amino]pyridine-3-carboxylicacid (350 mg) as sodium salt as an off white solid.

Step 9: Synthesis of4-[[6-(5-chloro-2-fluoro-phenyl)-3-isopropyl-2-pyridyl]amino]-N-(2-hydroxypropyl)pyridine-3-carboxamide

To a solution of4-[[6-(5-chloro-2-fluoro-phenyl)-3-isopropyl-2-pyridyl]amino]pyridine-3-carboxylicacid (50 mg, 0.123 mmol) in DMF (1.5 mL) was added DIPEA (0.06 mL, 0.369mmol) followed by addition of HATU (93 mg, 0.246 mmol). After 15 min, tothis reaction mixture was added (S)-1-aminopropan-2-ol (18 mg, 0.23mmol). The reaction mixture was heated at 100° C. overnight. Theprogress of reaction was monitored by LCMS. After completion of thereaction, the mixture was quenched by addition of water (5 mL) and theproduct was extracted with EtOAc (2×50 mL). The combined organic layerwas dried over sodium sulfate and concentrated under reduced pressure togive a crude product. The crude product was purified by reverse phasepreparative HPLC to afford4-[[6-(5-chloro-2-fluoro-phenyl)-3-isopropyl-2-pyridyl]amino]-N-(2-hydroxypropyl)pyridine-3-carboxamide (11.89 mg) as an off white solid.

NMR: ¹H NMR (400 MHz, CD₃OD) δ (ppm): 8.84-8.69 (m, 2H), 8.34 (d, J=6.1Hz, 1H), 8.00 (dd, J=6.8, 2.7 Hz 1H), 7.79 (d, J=8.0 Hz, 1H), 7.57-7.49(m, 1H), 7.42 (m, 1H), 7.25 (dd, J=10.9, 8.9 Hz, 1H), 4.01 (q, J=6.1 Hz,1H), 3.45 (d, J=4.7 Hz, 2H), 3.37 (dd, J=13.3, 6.9 Hz, 2H), 3.23 (dd,J=13.7, 6.8 Hz, 1H), 1.37 (d, J=6.8 Hz, 6H), 1.24 (d, J=6.3 Hz, 3H).

Example 1. Preparation of Compound Nos. 1, 1a and 1b Synthesis of4-[[5-bromo-2-(5-chloro-2-fluoro-phenyl)-4-pyridyl]amino]-N-(2-hydroxypropyl)pyridine-3-carboxamide

Step 1: Synthesis of 2,5-dibromo-4-iodo-pyridine

To a solution of diisopropylamine (3.24 mL, 0.023 mol) in anhydrous THF(50 mL) was added a 2M solution of n-BuLi in n-hexane (11.6 mL, 0.023mol) at −70° C. under nitrogen atmosphere. The reaction mixture wasstirred at −70° C. for 30 min. To this reaction mixture was added2,5-dibromopyridine (5 g, 0.021 mol) in THF (30 mL) dropwise. Thereaction mixture was stirred at −70° C. for 4 h. To the reactionmixture, then was added a solution of iodine (6.96 g, 0.0274 mol) in THF(20 mL) and stirred for 30 min at the same temperature. The progress ofreaction was monitored by TLC & ¹H NMR After completion of reaction, themixture was quenched using aqueous Sodium thiosulfate solution and theproduct was extracted with EtOAc. The organic layer was washed withaqueous sodium thiosulfate solution and brine solution. The organiclayer was dried over anhydrous sodium sulfate and concentrated underreduced pressure to afford 2,5-dibromo-4-iodo-pyridine (7.3 g) as ayellow solid pure compound.

Step 2: Synthesis of methyl4-[(2,5-dibromo-4-pyridyl)amino]pyridine-3-carboxylate

To a suspension of 2,5-dibromo-4-iodo-pyridine (3.5 g, 0.0096 mol)methyl 4-aminopyridine-3-carboxylate (1.615 g, 0.0106 mol) and potassiumphosphate tribasic (4.095 g, 0.0193 mol) in dioxane (20 mL) was purgedwith nitrogen for 45 min at RT. Then, to this reaction mixture was addedXantphos (0.837 g, 0.00144 mol) and Pd₂(dba)₃ (1.397 g, 0.00144 mol) andpurging with nitrogen was continued for 10 min. The reaction mixture washeated at 110° C. overnight. The progress of reaction was monitored byTLC and LCMS. After completion of reaction, the mixture was filteredthrough a celite bed and the celite bed was washed with EtOAc. Thefiltrate was concentrated under reduced pressure to obtain crudecompound that was purified by column chromatography on silica (100:200mesh) using 40% EtOAc-hexane system as eluent to afford methyl4-[(2,5-dibromo-4-pyridyl)amino]pyridine-3-carboxylate pure compound(1.510 g) as a yellow solid.

Step 3: Synthesis of methyl4-[[5-bromo-2-(5-chloro-2-fluoro-phenyl)-4-pyridyl]amino]pyridine-3-carboxylate

To a suspension of methyl4-[(2,5-dibromo-4-pyridyl)amino]pyridine-3-carboxylate (1.5 g, 0.0038mol), (5-chloro-2-fluoro-phenyl) boronic acid (1.014 g, 0.0058 mol) andsodium carbonate (0.823 g, 0.0077 mol) in toluene (20 mL) was purgedwith nitrogen for 45 min at RT. To this reaction mixture was addedPd(PPh₃)₄ (0.224 g, 0.00019 mol) and purging with nitrogen was continuedfor a further 10 min. The reaction mixture was heated at 100° C.overnight. After completion of reaction, the mixture was diluted withwater and the product was extracted with EtOAc. The organic layer waswashed with water and brine solution, dried over anhydrous sodiumsulfate and concentrated under reduced pressure to obtain crude compoundthat was purified by column chromatography on silica (100:200 mesh)using 35-40% EtOAc-hexane system as eluent to afford methyl4-[[5-bromo-2-(5-chloro-2-fluoro-phenyl)-4-pyridyl]amino]pyridine-3-carboxylate(1.07 g) in pure form.

Step 4: Synthesis of4-[[5-bromo-2-(5-chloro-2-fluoro-phenyl)-4-pyridyl]amino]pyridine-3-carboxylicacid

To a suspension of methyl4-[[5-bromo-2-(5-chloro-2-fluoro-phenyl)-4-pyridyl]amino]pyridine-3-carboxylate(665 mg, 1.522 mmol) in MeOH (5 mL) was added a solution of NaOH (91 mg,2.284 mmol) in water (1 mL). The reaction mixture was heated at 80° C.for 1 h. The progress of reaction was monitored by TLC. After completionof reaction, the mixture was concentrated under reduced pressure toobtain a sticky compound. To this reaction mixture was added toluene(3×10 mL) to obtain a solid compound which was triturated with diethylether (10 mL) to afford4-[[5-bromo-2-(5-chloro-2-fluoro-phenyl)-4-pyridyl]amino]pyridine-3-carboxylicacid (550 mg) as a light yellow solid.

Step 5: Synthesis of (5-chloro-2-fluoro-phenyl)boronic acid

To a solution of 2-bromo-4-chloro-1-fluoro-benzene (5 g, 0.0238 mol) inanhydrous diethyl ether (30 mL) was added a 2M solution of n-BuLi inn-hexane (13 mL, 0.0262 mole) at −70° C. under nitrogen atmosphere. Thesolution was stirred for 30 min at the same temperature, and thentriisopropyl borate (4.93 g, 0.0262 mol) was added dropwise in to thesolution. The white slurry that formed was stirred for 30 min at −70° C.and then warmed to RT and stirred for 1 h. The reaction was monitored byTLC and ¹H NMR. After completion of reaction, the reaction mixture washydrolyzed with 6 N NaOH and stirred for 1 h. The reaction mixture wasextracted with EtOAc. The organic layer was washed with brine andconcentrated under reduced pressure to obtain a sticky compound that wastriturated with n-Pentane and dried to afford(5-chloro-2-fluoro-phenyl)boronic acid (2.2 g) as an off white solid.

Step 6: Synthesis of4-[[5-bromo-2-(5-chloro-2-fluoro-phenyl)-4-pyridyl]amino]-N-(2-hydroxypropyl)pyridine-3-carboxamide

To a solution of4-[[5-bromo-2-(5-chloro-2-fluoro-phenyl)-4-pyridyl]amino]pyridine-3-carboxylicacid (550 mg, 1.241 mmol) in DMF (5 mL) was added N,N-diisopropylethylamine (0.65 mL, 3.725 mmol) and HATU (755 mg, 1.986 mmol). The reactionmixture was stirred at RT for 15 min under nitrogen atmosphere. Then, tothis reaction mixture was added (S)-1-aminopropan-2-ol (233 mg, 3.104mmol) and the reaction mixture was stirred at 35° C. overnight. Theprogress of reaction was monitored by TLC. After completion of reaction,the mixture was diluted with water and extracted with EtOAc (100 mL).The organic layer was washed with water (100 mL) and brine solution (100mL), dried over anhydrous sodium sulfate and concentrated under reducedpressure to obtain crude product. The crude product was purified byreverse phase HPLC to afford4-[[5-bromo-2-(5-chloro-2-fluoro-phenyl)-4-pyridyl]amino]-N-(2-hydroxypropyl)pyridine-3-carboxamide (11 mg) as a white solid. The (R) enantiomer canbe synthesized utilizing (R)-1-aminopropan-2-ol in this step.

NMR: ¹H NMR (400 MHz. CDCl₃) δ (ppm): 10.62 (s, 1H), 8.75 (d, J=5.7 Hz,2H), 8.50 (d, J=5.9 Hz, 1H), 8.03 (dd, J=6.8, 2.7 Hz, 1H), 7.88 (s, 1H),7.47 (d, J=5.8 Hz, 1H), 7.35 (m, 1H), 7.11 (dd, J=10.8, 8.7 Hz, 1H),6.76 (s, 1H), 4.09 (m, 1H), 3.76 (m, 1H), 3.31 (m, 1H), 1.34-1.23 (d,3H).

Example 2. Preparation of Compound Nos. 2, 2a and 2b Synthesis of(S)-4-[[2-(5-chloro-2-fluoro-phenyl)-5-isopropyl-4-pyridyl]amino]-N-(2-hydroxypropyl)pyridine-3-carboxamide

Step 1: Synthesis of 2-(4,6-dichloro-3-pyridyl)propan-2-ol

To a solution of (5 g, 0.0243 mol) in dry THF (60 mL) was added a 3Msolution of methylmagnesium bromide in diethyl ether (28.3 mL, 0.0848mol) dropwise under nitrogen at −60° C. The reaction mixture was stirredat −60° C. to 0° C. for 2 h. The progress of reaction was monitored byTLC & ¹H NMR. After completion of the reaction, the mixture was quenchedwith a saturated aqueous solution of ammonium chloride and extractedwith EtOAc. The organic layer was washed water and brine solution, driedover anhydrous sodium sulfate and concentrated under reduced pressure toafford 2-(4,6-dichloro-3-pyridyl)propan-2-ol (4.96 g) in pure form as ayellow oily substance.

Step 2: Synthesis of2-[4-chloro-6-(5-chloro-2-fluoro-phenyl)-3-pyridyl]propan-2-ol

A suspension of 2-(4,6-dichloro-3-pyridyl)propan-2-ol (4.96 g, 0.024mole), (5-chloro-2-fluoro-phenyl)boronic acid (6.284 g, 0.036 mol) andsodium bicarbonate (4.045 g, 0.048 mol) in a 2:1 mixture of DMF:H₂O (60mL) was purged with nitrogen for 45 min. Then, to this reaction mixturewas added Pd(PPh₃)₄ (500 mg) and purging continued with nitrogen for 10min. The reaction mixture was heated at 80° C. overnight. Aftercompletion of reaction, the reaction mixture was diluted with water, andthe product was extracted with EtOAc. The organic layer was washed withwater and brine solution, then dried over anhydrous sodium sulfate andconcentrated under reduced pressure to obtain crude product. The crudeproduct was purified by column chromatography on silica gel (100:200mesh) using 7% EtOAc-hexane system as eluent to afford2-[4-chloro-6-(5-chloro-2-fluoro-phenyl)-3-pyridyl]propan-2-ol (4.931 g)pure compound as an off white solid.

Step 3: Synthesis of4-chloro-2-(5-chloro-2-fluoro-phenyl)-5-isopropenyl-pyridine

To a solution of2-[4-chloro-6-(5-chloro-2-fluoro-phenyl)-3-pyridyl]propan-2-ol (4.931 g,0.0165 mol) in O-xylene (60 mL) was added PTSA.H₂O (0.313 g, 0.00165mol) and hydroquinone (0.181 g, 0.00165 mol) and heated at 160° C. inDean Stark apparatus overnight. The progress of reaction was monitoredby TLC and ¹H NMR. After completion of reaction, the mixture wasconcentrated under reduced pressure to obtain crude product. The crudeproduct was purified by column chromatography on silica gel (100:200mesh) using 10% EtOAc-hexane to afford4-chloro-2-(5-chloro-2-fluoro-phenyl)-5-isopropenyl-pyridine (4 g) purecompound.

Step 4: Synthesis of4-[[2-(5-chloro-2-fluoro-phenyl)-5-isopropenyl-4-pyridyl]amino]pyridine-3-carboxylate

To a suspension of4-chloro-2-(5-chloro-2-fluoro-phenyl)-5-isopropenyl-pyridine (1 g, 3.55mmol), methyl 4-aminopyridine-3-carboxylate (0.595 g, 0.0039 mol) andpotassium phosphate tribasic (1.510 g, 0.0071 mol) in dioxane (20 mL)was purged with nitrogen for 45 min. To this reaction mixture was addedXantphos (0.308 g, 0.0053 mol) and Pd₂(dba)₃ (0.552 g, 0.0053 mol) andpurging continued with nitrogen for 10 min. The reaction mixture washeated at 100° C. for 16 h. The progress of reaction was monitored byTLC and LCMS. After completion of reaction, the reaction mixture wasfilter through a celite bed, and the celite bed was washed with EtOAc.The filtrate was concentrated under reduced pressure to obtain the crudeproduct. The crude product was purified by column chromatography onsilica gel (100:200 mesh) using 30-35% EtOAc-hexane as eluent to affordmethyl4-[[2-(5-chloro-2-fluoro-phenyl)-5-isopropenyl-4-pyridyl]amino]pyridine-3-carboxylate(0.7 g) pure compound as a yellow solid.

Step 5: Synthesis of methyl4-[[2-(5-chloro-2-fluoro-phenyl)-5-isopropyl-4-pyridyl]amino]pyridine-3-carboxylate

To a stirred solution of methyl4-[[2-(5-chloro-2-fluoro-phenyl)-5-isopropenyl-4-pyridyl]amino]pyridine-3-carboxylate(360 mg, 0.906 mmol) in ethanol (5 mL) was added PtO₂ (80 mg). Thereaction mixture was stirred at RT for 18 h under hydrogen atmosphereusing a hydrogen bladder. The progress of reaction was monitored by ¹HNMR. After completion of reaction, the mixture was filtered through acelite bed, and the celite bed was washed with EtOAc (2×50 mL). Thefiltrate was collected and concentrated under reduced pressure to affordmethyl4-[[2-(5-chloro-2-fluoro-phenyl)-5-isopropyl-4-pyridyl]amino]pyridine-3-carboxylate(350 mg) as a sticky oily substance.

Step 6: Synthesis of(S)-4-[[2-(5-chloro-2-fluoro-phenyl)-5-isopropyl-4-pyridyl]amino]-N-(2-hydroxypropyl)pyridine-3-carboxamide

To a stirred solution of (S)-1-aminopropan-2-ol (86 mg, 1.14 mmol) inDCM (10 mL) was added potassium tert-butoxide (128 mg, 1.14 mmol). Thereaction mixture was stirred at RT for 10 min under nitrogen atmosphere.Then, to this reaction mixture was added a solution of methyl4-[[2-(5-chloro-2-fluoro-phenyl)-5-isopropyl-4-pyridyl]amino]pyridine-3-carboxylate(350 mg, 0.877 mmol) in DCM (10 mL) dropwise. The reaction mixture washeated at 55° C. for 1 h. The progress of reaction was monitored by TLCand LCMS. After completion of reaction, the mixture was diluted with DCM(50 mL) and washed with water (30 mL) and brine solution (20 mL). Theorganic layer was dried over anhydrous sodium sulfate, and concentratedunder reduced pressure to obtain the crude product. The crude productwas purified by reverse phase HPLC to afford(S)-4-[[2-(5-chloro-2-fluoro-phenyl)-5-isopropyl-4-pyridyl]amino]-N-(2-hydroxypropyl)pyridine-3-carboxamide(13 mg) as the TFA salt. The (R) enantiomer can be synthesized utilizing(R)-1-aminopropan-2-ol in this step.

NMR: ¹H NMR (400 MHz, CD₃OD) δ (ppm): 8.92 (s, 1H), 8.77 (s, 1H), 8.37(d, J=7.1 Hz, 1H), 7.99-7.90 (m, 2H), 7.54 (m, 1H), 7.46 (d, J=7.0 Hz,1H), 7.31 (t, J=9.7 Hz, 1H), 4.07-3.94 (m, 1H), 3.49 (m, 1H), 3.37 (m,1H), 3.32-3.21 (m, 1H), 1.40 (d, J=6.9 Hz, 6H), 1.24 (d, J=6.3 Hz, 3H).

Example 3. Preparation of Compound Nos. 3, 3a and 3b Synthesis of(S)-4-(2-(5-chloro-2-fluorophenyl)-5-(prop-1-en-2-yl)pyridin-4-ylamino)-N-(2-hydroxypropyl)pyridine-5-carboxamide

Steps 1 to 4 are the same as in Example 2.

Step 5: Synthesis of(S)-4-(2-(5-chloro-2-fluorophenyl)-5-(prop-1-en-2-yl)pyridin-4-ylamino)-N-(2-hydroxypropyl)pyridine-5-carboxamide

To a stirred solution of (S)-1-aminopropan-2-ol (92 mg, 1.227 mmol) inDCM (10 mL) was added potassium tertiary butoxide (138 mg, 1.227 mmol).The reaction mixture was stirred at RT for 10 min under nitrogenatmosphere. Then, to this stirred reaction mixture was added a solutionof methyl4-[[2-(5-chloro-2-fluoro-phenyl)-5-isopropenyl-4-pyridyl]amino]pyridine-3-carboxylate(375 mg, 0.944 mmol) in DCM (10 mL) dropwise. The reaction mixture washeated at 55° C. for 1 h. The progress of reaction was monitored by TLCand LCMS. After completion of reaction, the mixture was diluted with DCM(60 mL), washed with water (40 mL) and brine solution (20 mL). Theorganic layer was dried over anhydrous sodium sulfate and concentratedunder reduced pressure to obtain the crude product. The crude productwas purified by reverse phase HPLC to afford(S)-4-(2-(5-chloro-2-fluorophenyl)-5-(prop-1-en-2-yl)pyridin-4-ylamino)-N-(2-hydroxypropyl)pyridine-5-carboxamide(31 mg) as a white solid. The (R) enantiomer can be synthesizedutilizing (R)-1-aminopropan-2-ol in this step.

NMR: ¹H NMR (400 MHz, CDCl₃) δ (ppm): 10.21 (s, 1H), 8.68 (s, 1H), 8.50(s, 1H), 8.44-8.37 (m, 1H), 8.03 (dd, J=6.8, 2.8 Hz, 1H), 7.81 (d, J=1.8Hz, 1H), 7.43-7.24 (m, 2H), 7.10 (t, J=9.7 Hz, 1H), 6.76 (s, 1H), 5.51(s, 1H), 5.23 (s, 1H), 4.13-4.00 (m, 1H), 3.70 (m, 1H), 3.29 (m, 1H),2.14 (d, J=1.4 Hz, 3H), 1.29 (d, J=6.3 Hz, 3H).

Example 4. Preparation of Compound Nos. 4, 4a and 4b Synthesis of(S)-4-(2-(5-chloro-2-fluorophenyl)-5-(prop-1-en-2-yl)pyridin-4-ylamino)-N-(2-hydroxypropyl)pyrimidine-5-carboxamide

Steps 1 to 3 are the same as in Example 2.

Step 4: Synthesis of 4-aminopyrimidine-5-carboxylic acid

To a stirred solution of 4-aminopyrimidine-5-carboxylic acid (1 g, 7.188mmol) in MeOH (20 mL) was added concentrated sulfuric acid (4 mL)dropwise at 0° C. The reaction mixture was heated to reflux at 85° C. ina reagent bottle overnight. The progress of reaction was monitored by ¹HNMR. After completion of reaction, the mixture was concentrated underreduced pressure to remove MeOH. To the residue was added ice-water (10mL) and the pH of the aqueous mixture was made neutral by the additionof a saturated solution of sodium bicarbonate. The product was extractedwith EtOAc (2×50 mL). The organic layer was again washed with brinesolution (40 mL). The organic layer was separated, dried over anhydroussodium sulfate and concentrated under reduced pressure to afford4-aminopyrimidine-5-carboxylic acid (780 mg) as an off-white solid.

Step 5: Synthesis of methyl4-[[2-(5-chloro-2-fluoro-phenyl)-5-isopropenyl-4-pyridyl]amino]pyrimidine-5-carboxylate

A solution of4-chloro-2-(5-chloro-2-fluoro-phenyl)-5-isopropenyl-pyridine (440 mg,1.559 mmol), methyl 4-aminopyrimidine-5-carboxylate (263 mg, 1.715 mmol)and potassium phosphate (tribasic) (662 mg, 3.118 mmol) in 1,4-dioxane(20 mL) was purged with nitrogen for 30 min. Then, to this reactionmixture was added tris(dibenzylidineacetone)dipalladium(0) (143 mg,0.156 mmol) and Xantphos (135 mg, 0.233 mmol). Then, to this reactionmixture was purged with nitrogen gas for another 5 min. The reactionmixture was heated at 100° C. overnight. The progress of reaction wasmonitored by TLC and LCMS. After completion of reaction, the mixture wasdiluted with EtOAc (50 mL) and filtered through a celite bed. Thefiltrate was washed with water (20 mL) and finally with brine solution(20 mL). The organic layer was separated, dried over anhydrous sodiumsulfate and concentrated under reduced pressure to afford crude productwhich was purified by CombiFlash® chromatography using 20% EtOAc-hexanesystem as eluent to afford methyl4-[[2-(5-chloro-2-fluoro-phenyl)-5-isopropenyl-4-pyridyl]amino]pyrimidine-5-carboxylate(325 mg) as a light yellow solid.

Step 6: Synthesis of(S)-4-(2-(5-chloro-2-fluorophenyl)-5-(prop-1-en-2-yl)pyridin-4-ylamino)-N-(2-hydroxypropyl)pyrimidine-5-carboxamide

To a stirred solution of methyl4-[[2-(5-chloro-2-fluoro-phenyl)-5-isopropenyl-4-pyridyl]amino]pyrimidine-5-carboxylate(100 mg, 0.250 mmol) and (S)-1-amino-propan-2-ol (28 mg, 0.376 mmol) intoluene (8 mL) was added a 1 M solution of trimethylaluminium in heptane(1 mL, 1.00 mmol) at RT. The reaction mixture was heated at reflux for 2h. The progress of reaction was monitored by TLC. After completion ofreaction, the mixture was diluted with EtOAc (30 mL) and washed withsaturated solution of sodium bicarbonate (15 mL), water (15 mL) andbrine (15 mL). The organic layer was separated, dried over anhydroussodium sulfate, and concentrated under reduced pressure to afford crudeproduct. The crude product was purified by precipitating in DCM-Pentanesystem and dried to afford(S)-4-(2-(5-chloro-2-fluorophenyl)-5-(prop-1-en-2-yl)pyridin-4-ylamino)-N-(2-hydroxypropyl)pyrimidine-5-carboxamide(90 mg) as an off-white solid. The (R) enantiomer can be synthesizedutilizing (R)-1-aminopropan-2-ol in this step.

NMR: ¹H NMR (400 MHz, CD₃OD) δ (ppm): 9.56 (s, 1H), 9.15 (d, J=9.8 Hz,2H), 8.63 (s, 1H), 7.88 (dd, J=6.3, 2.7 Hz, 1H), 7.75 (ddd, J=9.1, 4.5,2.7 Hz, 1H), 7.48 (t, J=9.5 Hz, 1H), 5.88-5.64 (s, 1H), 5.45 (s, 1H),3.99 (td, J=6.8, 4.6 Hz, 1H), 3.52-3.34 (m, 2H), 2.72 (s, 9H), 2.25 (s,3H), 1.23 (d, J=6.3 Hz, 3H). LCMS: 442.2 (M+1).

Example 5. Preparation of Compound Nos. 5, 5a and 5b Synthesis of(S)-1-((4-(2-(5-chloro-2-fluorophenyl)-5-isopropylpyridin-4-ylamino)pyridin-3-yl)methylamino)propan-2-ol

Steps 1 to 7 are the same as in Comparative Example 1

Step 8: Synthesis of(S)-1-((4-(2-(5-chloro-2-fluorophenyl)-5-isopropylpyridin-4-ylamino)pyridin-3-yl)methylamino)propan-2-ol

To a solution of methyl4-[[2-(5-chloro-2-fluoro-phenyl)-5-isopropyl-4-pyridyl]amino]pyridine-3-carboxylate(100 mg, 0.25 mmol) in THF (10 mL) was added a 1 M solution of DIBAL-H(1.25 mL, 1.25 mmol) in toluene at 0° C. The reaction mixture wasstirred at RT overnight. The progress of reaction was monitored by TLCand LCMS. After completion of reaction, the mixture was quenched with anaqueous solution of NH₄Cl and extracted with EtOAc (50 mL). The combinedorganic layer was washed with water (20 mL), dried over anhydrous sodiumsulfate and concentrated under reduced pressure to obtain[4-[[2-(5-chloro-2-fluoro-phenyl)-5-isopropyl-4-pyridyl]amino]-3-pyridyl]methanol(70 mg).

Step 9: Synthesis of[4-[[2-(5-chloro-2-fluoro-phenyl)-5-isopropyl-4-pyridyl]amino]-3-pyridyl]methylmethanesulfonate

To a solution of[4-[[2-(5-chloro-2-fluoro-phenyl)-5-isopropyl-4-pyridyl]amino]-3-pyridyl]methanol(70 mg, 0.188 mmol) in DCM (5 mL) was added triethylamine (0.13 mL, 0.94mmol) at 0° C. After 10 min, to this reaction mixture was added methanesulfonyl chloride (0.03 mL, 0.376 mmol). The reaction mixture wasstirred at the same temperature for 2 h. The progress of reaction wasmonitored by TLC and LCMS. After completion of the reaction, the mixturewas diluted with DCM (15 mL) and washed with water (10 mL). The organiclayer was separated and further washed with water (20 mL). The organiclayer was dried over anhydrous sodium sulfate, and concentrated underreduced pressure to give[4-[[2-(5-chloro-2-fluoro-phenyl)-5-isopropyl-4-pyridyl]amino]-3-pyridyl]methylmethanesulfonate (40 mg).

Step 10: Synthesis of1-[[4-[[2-(5-chloro-2-fluoro-phenyl)-5-isopropyl-4-pyridyl]amino]-3-pyridyl]methylamino]propan-2-ol

To a solution of (2S)-1-aminopropan-2-ol (33 mg, 0.444 mmol) in DMF (3mL) was added NaH (10 mg, 0.22 mmol) at 0° C. The reaction mixture wasstirred for 30 min at the same temperature. To this stirred reactionmixture was added a solution of[4-[[2-(5-chloro-2-fluoro-phenyl)-5-isopropyl-4-pyridyl]amino]-3-pyridyl]methylmethanesulfonate (100 mg, 0.22 mmol) in DMF (2 mL). Then, the reactionmixture was stirred at 0° C. for 2 h. The progress of reaction wasmonitored by LCMS. After completion of the reaction, the mixture wasquenched with ice-cold water (10 mL) and extracted with EtOAc (50 mL).The organic layer was dried over anhydrous sodium sulfate andconcentrated under reduced pressure to obtain the crude product. Thecrude product was purified by reverse phase HPLC to give1-[[4-[[2-(5-chloro-2-fluoro-phenyl)-5-isopropyl-4-pyridyl]amino]-3-pyridyl]methylamino]propan-2-ol(8.9 mg). The (R) enantiomer can be synthesized utilizing(R)-1-aminopropan-2-ol in this step.

NMR: ¹H NMR (400 MHz, CDCl₃) δ (ppm): 8.83 (s, 1H), 8.75 (s, 1H),8.09-7.91 (m, 2H), 7.61 (s, 1H), 7.42-7.29 (m, 1H), 7.11-6.95 (m, 2H),6.71 (d, J=6.7 Hz, 1H), 4.52 (s, 2H), 4.25 (s, 1H), 3.23 (m, 1H), 3.11(m, 1H), 2.40 (m, 1H), 1.35 (m, 3H), 1.28 (m, 6H).

Example 6. Preparation of Compound Nos. 6, 6a and 6b Synthesis of(S)-4-(2-(5-chloro-2-fluorophenyl)-5-isopropylpyridin-4-ylamino)-N-(1-hydroxypropan-2-yl)nicotinamide

Steps 1 to 7 are the same as in Comparative Example 1

Step 8: Synthesis of(S)-4-(2-(5-chloro-2-fluorophenyl)-5-isopropylpyridin-4-ylamino)-N-(1-hydroxypropan-2-yl)nicotinamide

A suspension of (S)-2-aminopropan-1-ol (45 mg, 0.601 mmol), potassiumtert-butoxide (68 mg, 0.601 mmol) in DCM (5 mL) was stirred for 5 min.The reaction mixture turned yellow. To this reaction mixture was added asolution of methyl4-[[2-(5-chloro-2-fluoro-phenyl)-5-isopropyl-4-pyridyl]amino]pyridine-3-carboxylate(200 mg, 0.503 mmol) in DCM (5 mL). Then, this reaction mixture washeated in a closed reagent bottle at 55° C. for 1 h. The progress ofreaction was monitored by TLC and LCMS. After completion of thereaction, the reaction mixture was diluted with DCM (15 mL) and water (5mL). The DCM layer was separated. The aqueous layer was again extractedwith DCM (15 mL). The combined organic layer was dried over anhydroussodium sulfate, and concentrated under reduced pressure to afford acrude product which was purified by reverse phase HPLC to afford(S)-4-(2-(5-chloro-2-fluorophenyl)-5-isopropylpyridin-4-ylamino)-N-(1-hydroxypropan-2-yl)nicotinamide(42.12 mg) as a white solid. The (R) enantiomer can be synthesizedutilizing (R)-2-aminopropan-1-ol in this step.

NMR: ¹H NMR (400 MHz, CD₃OD) δ (ppm): 8.76 (s, 1H), 8.59 (s, 1H), 8.32(d, J=6.0 Hz, 1H), 7.89 (dd, J=6.7, 2.7 Hz, 1H), 7.80 (s, 1H), 7.45 (t,J=5.2 Hz, 1H), 7.37 (d, J=6.1 Hz, 1H), 7.25 (t, J=9.75 Hz, 1H), 4.24 (h,J=6.4 Hz, 1H), 3.62 (m, 2H), 3.25 (m, 1H), 1.40 (dd, J=7.0, 1.6 Hz, 6H),1.26 (d, J=6.8 Hz, 3H).

Example 7a. Preparation of Compound No. 7a Synthesis of(S)-4-(2-(5-chloro-2-fluorophenyl)-5-(prop-1-en-2-yl)pyridin-4-ylamino)-N-(1-hydroxypropan-2-yl)nicotinamide

Steps 1 to 4 are the same as in Example 2

Step 5: Synthesis of(S)-4-(2-(5-chloro-2-fluorophenyl)-5-(prop-1-en-2-yl)pyridin-4-ylamino)-N-(1-hydroxypropan-2-yl)nicotinamide

A suspension of (S)-2-aminopropan-1-ol (45 mg, 0.601 mmol) andtert-butoxide (68 mg, 0.601 mmol) in DCM (5 mL) was stirred for 5 min.The reaction mixture turned yellow. To this reaction mixture was added asolution of methyl4-[[2-(5-chloro-2-fluoro-phenyl)-5-isopropenyl-4-pyridyl]amino]pyridine-3-carboxylate(200 mg, 0.501 mmol) in DCM (5 mL). Then, the reaction mixture washeated in a closed reagent bottle at 55° C. for 1 h. The progress ofreaction was monitored by TLC and LCMS. After completion of thereaction, the mixture was diluted with DCM (15 mL) and water (5 mL). TheDCM layer was separated. The aqueous layer was again extracted with DCM(15 mL). The combined organic layer was dried over anhydrous sodiumsulfate. Removal of DCM under reduced pressure afforded a crude productwhich was purified by reverse phase HPLC to afford(5)-4-(2-(5-chloro-2-fluorophenyl)-5-(prop-1-en-2-yl)pyridin-4-ylamino)-N-(1-hydroxypropan-2-yl)nicotinamide(66 mg) as a white solid.

NMR: ¹H NMR (400 MHz, DMSO-d6) δ (ppm): 10.78 (s, 1H), 8.84 (s, 1H),8.66 (d, J=7.9 Hz, 1H), 8.56 (s, 1H), 8.40 (d, J=6.2 Hz, 1H), 8.00 (dd,J=6.8, 2.8 Hz, 1H), 7.85 (s, 1H), 7.57 (dt, J=8.7, 3.6 Hz, 1H),7.47-7.37 (m, 2H), 5.47 (s, 1H), 5.22 (s, 1H), 4.84-4.74 (m, 1H), 4.03(m, 1H), 3.50-3.35 (m, 1H), 2.08 (s, 3H), 1.13 (d, J=6.7 Hz, 3H).

Example 7b. Preparation of Compound No. 7b Synthesis of4-[[2-(5-chloro-2-fluoro-phenyl)-5-isopropenyl-4-pyridyl]amino]-N-(2-hydroxy-1-methyl-ethyl)pyridine-3-carboxamide

Steps 1 to 4 are the same as in Example 2

Step 5: Synthesis of(2R)-4-[[2-(5-chloro-2-fluoro-phenyl)-5-isopropenyl-4-pyridyl]amino]-N-(2-hydroxy-1-methyl-ethyl)pyridine-3-carboxamide

To methyl4-[[2-(5-chloro-2-fluoro-phenyl)-5-isopropenyl-4-pyridyl]amino]pyridine-3-carboxylate(100 mg, 0.25 mmol) and (2R)-2-aminopropan-1-ol (37 mg, 0.5 mmol) intoluene (4 mL) was added Me₃Al (1.0 mL, 1.00 mmol). The reaction mixturewas heated at 140° C. for 4 h. The progress of reaction was monitored byLCMS. After completion reaction, the mixture was quenched with asaturated aqueous solution of NaHCO₃ (20 mL) and the product wasextracted with EtOAc (2×70 mL). The combined organic layer was washedwith brine (30 mL), dried over sodium sulfate and concentrated underreduced pressure to give a crude product. The crude product was purifiedby preparative HPLC to afford(2R)-4-[[2-(5-chloro-2-fluoro-phenyl)-5-isopropenyl-4-pyridyl]amino]-N-(2-hydroxy-1-methyl-ethyl)pyridine-3-carboxamide(13.25 mg).

NMR: ¹H NMR (400 MHz, CDCl₃) δ (ppm): 10.55 (s, 1H), 8.94 (s, 1H), 8.54(s, 1H), 8.32 (d, J=6.4 Hz, 1H), 8.03 (dd, J=6.7, 2.7 Hz, 1H), 7.79 (d,J=1.7 Hz, 1H), 7.39-7.25 (m, 3H), 7.09 (dd, J=10.7, 8.7 Hz, 1H), 5.50(d, J=2.2 Hz, 1H), 5.23 (s, 1H), 4.28 (m, 1H), 3.82 (dd, J=11.4, 3.5 Hz,1H), 3.70 (dd, J=11.3, 5.6 Hz, 1H), 2.13 (s, 3H), 1.32 (d, J=6.7 Hz,3H). LCMS: 441.2 (M+1).

Example 8. Preparation of Compound No. 8 Synthesis of4-[[2-(5-chloro-2-fluoro-phenyl)-5-isopropenyl-4-pyridyl]amino]-N-(2-hydroxy-1,1-dimethyl-ethyl)pyridine-3-carboxamide

Steps 1 to 4 are the same as in Example 2

Step 5: Synthesis of4-[[2-(5-chloro-2-fluoro-phenyl)-5-isopropenyl-4-pyridyl]amino]-N-(2-hydroxy-1,1-dimethyl-ethyl)pyridine-3-carboxamide

To a solution of 2-amino-2-methyl-propan-1-ol (24 mg, 0.27 mmol) in DCM(3 mL) was added potassium tertiary butoxide (33 mg, 0.30 mmol). Thereaction mixture was stirred at RT for 20 min. To the stirred reactionmixture was added a solution of methyl4-[[2-(5-chloro-2-fluoro-phenyl)-5-isopropenyl-4-pyridyl]amino]pyridine-3-carboxylate(100 mg, 0.25 mmol) in DCM (5 mL) dropwise at RT. The reaction mixturewas heated at 50° C. for 1 h. After completion of reaction, water (50mL) was added and the mixture was diluted with DCM (50 mL). The organiclayer was washed with brine (20 mL) and concentrated under reducedpressure to give a crude product which was purified by reverse phaseHPLC to give of4-[[2-(5-chloro-2-fluoro-phenyl)-5-isopropenyl-4-pyridyl]amino]-N-(2-hydroxy-1,1-dimethyl-ethyl)pyridine-3-carboxamide(17.96 mg) as a white solid.

NMR: ¹H NMR (400 MHz; CD₃OD) δ (ppm): 8.65 (s, 1H), 8.42 (s, 1H), 8.35(d, J=5.9 Hz, 1H), 7.90 (dd, J=6.7, 2.7 Hz, 1H), 7.82 (s, 1H), 7.46 (m,2H), 7.26 (m, 1H), 5.53 (s, 1H), 5.23 (s, 1H), 3.72 (s, 2H), 2.15 (s,3H), 1.40 (s, 6H).

Example 9. Preparation of Compound No. 9 Synthesis of[4-[[2-(5-chloro-2-fluoro-phenyl)-5-isopropyl-4-pyridyl]amino]-3-pyridyl]-(4-hydroxy-1-piperidyl)methanone

Steps 1 to 8 are the same as in Comparative Example 1

Step 9: Synthesis of[4-[[2-(5-chloro-2-fluoro-phenyl)-5-isopropyl-4-pyridyl]amino]-3-pyridyl]-(4-hydroxy-1-piperidyl)methanone

To a solution of4-[[2-(5-chloro-2-fluoro-phenyl)-5-isopropyl-4-pyridyl]amino]pyridine-3-carboxylic acid (140 mg, 0.343 mmol) in DMF (4 mL) was addedN,N-diisopropylethyl amine (0.23 mL, 1.37 mmol) and HATU (254 mg, 0.686mmol). The reaction mixture was stirred at RT for 15 min under nitrogenatmosphere. To this stirred reaction mixture was added piperidin-4-ol(41 mg, 0.411 mmol) in DMF (1 mL) and the reaction mixture was stirredat RT overnight. The progress of reaction was monitored by TLC. Aftercompletion of the reaction, the mixture was diluted with water andextracted with EtOAc (50 mL). The organic layer was washed with water(2×10 mL) and brine solution (10 mL). The combined organic layer wasdried over anhydrous sodium sulfate and evaporated under reducedpressure to obtain oily crude compound that was purified by reversephase HPLC to afford[4-[[2-(5-chloro-2-fluoro-phenyl)-5-isopropyl-4-pyridyl]amino]-3-pyridyl]-(4-hydroxy-1-piperidyl)methanone(9 mg).

NMR: ¹H NMR (400 MHz, CDCl₃) δ (ppm): 8.76 (s, 1H), 8.60 (s, 1H), 8.40(d, J=14.5 Hz, 2H), 8.02 (dd, J=6.8, 2.7 Hz, 1H), 7.76 (s, 1H),7.39-7.27 (m, 2H), 7.09 (dd, J=10.7, 8.8 Hz, 1H), 4.10-4.01 (m, 3H),3.51 (m, 2H), 3.13 (p, J=6.9 Hz, 1H), 1.99 (m, 2H), 1.7 (m, 2H), 1.38(d, J=6.8 Hz, 6H).

Example 10. Preparation of Compound Nos. 10, 10a and 10b Synthesis of(S)-4-(2-(5-chloro-2-fluorophenyl)-5-vinylpyridin-4-ylamino)-N-(2-hydroxypropyl)nicotinamide

Step 1: Synthesis of (4,6-dichloro-3-pyridyl)methanol

To a solution of methyl 4,6-dichloropyridine-3-carboxylate (1 g, 4.854mmol) in anhydrous THF (25 mL) was added a 1 M solution ofdiisobutylaluminium hydride in toluene (14.5 mL, 14.5 mmol) dropwiseunder nitrogen atmosphere at −78° C. The reaction mixture was stirredfor 2 h during which reaction mixture slowly warmed to 0° C. Theprogress of reaction was monitored by TLC. After completion of reaction,the mixture was quenched with saturated ammonium chloride solution (20mL). EtOAc (100 mL) was added to the reaction mixture which wasfiltered. The filtrate was washed with water (30 mL) followed by brinewash (30 mL). The organic layer was separated, dried over anhydroussodium sulfate and concentrated under reduced pressure to afford(4,6-dichloro-3-pyridyl)methanol (820 mg) as a white solid.

Step 2: Synthesis of 4,6-dichloropyridine-3-carbaldehyde

A solution of oxalyl chloride (2.32 mL, 26.963 mmol) in DCM (30 mL) wascooled down to −78° C. To this solution was added DMSO (3.83 mL, 53.922mmol) dropwise under nitrogen atmosphere. The reaction mixture wasstirred at the same temperature for another 30 min. To this reactionmixture was added a solution of (4,6-dichloro-3-pyridyl)methanol (1.6 g,8.987 mmol) in DCM (10 mL), and then the reaction mixture was stirredfor 30 min. Then, to this stirred reaction mixture was addedtriethylamine (11.2 mL, 80.883 mmol). The reaction mixture was stirredat the same temperature for another 30 min. The progress of reaction wasmonitored by TLC. After completion of reaction, the mixture was quenchedwith saturated sodium bicarbonate solution (30 mL). The product wasextracted using DCM (2×50 mL). The combined organic layer was againwashed with water (3×30 mL) and finally with brine solution (30 mL). Theorganic layer was separated, dried over anhydrous sodium sulfate andconcentrated under reduced pressure to afford4,6-dichloropyridine-3-carbaldehyde (1.53 g) as a light yellow solid.

Step 3: Synthesis of 1-(4,6-dichloro-3-pyridyl)ethanol

To a solution of 4,6-dichloropyridine-3-carbaldehyde (1.53 g, 8.693mmol) in anhydrous THF (15 mL) was added a 3M solution ofmethylmagnesium bromide in diethyl ether (5.8 mL, 17.386 mmol) dropwiseunder nitrogen atmosphere at −78° C. The reaction mixture was stirredfor 1 h during which the reaction mixture slowly warmed to 0° C. Theprogress of reaction was monitored by TLC. After completion of reaction,the mixture was quenched with saturated ammonium chloride solution (15mL). The product was extracted using EtOAc (2×25 mL). The combinedorganic layer was again washed with water (20 mL) and finally with brinesolution (20 mL). The organic layer was separated, dried over anhydroussodium sulfate and concentrated under reduced pressure to afford1-(4,6-dichloro-3-pyridyl)ethanol (1.56 g) as a light brown liquid.

Step 4: Synthesis of1-[4-chloro-6-(5-chloro-2-fluoro-phenyl)-3-pyridyl]ethanol

A mixture of 1-(4,6-dichloro-3-pyridyl)ethanol (1.56 g, 8.123 mmol),(5-chloro-2-fluoro-phenyl)boronic acid (2.12 g, 12.184 mmol) and sodiumbicarbonate (1.36 g, 16.246 mmol) in a 2:1 mixture of DMF:H₂O (21 mL)was purged with nitrogen gas for 40 min. To this reaction mixture wasadded bis(triphenylphosphine)palladium(II) dichloride (285 mg, 0.406mmol) and then was purged with nitrogen gas for another 5 min. Thereaction mixture was heated at 100° C. overnight. The progress ofreaction was monitored by TLC and LCMS. After completion of reaction,water (20 mL) was added to the reaction mixture and product wasextracted with EtOAc (2×25 mL). The combined organic layer was washedwith water (3×25 mL) and finally with brine solution (25 mL). Theorganic layer was separated, dried over anhydrous sodium sulfate andconcentrated under reduced pressure to afford crude product which waspurified by column chromatography on silica gel (100-200 mesh) using 6%EtOAc:Hexane system as eluent to afford1-[4-chloro-6-(5-chloro-2-fluoro-phenyl)-3-pyridyl]ethanol (1.2 g) as alight brown liquid.

Step 5: Synthesis of4-chloro-2-(5-chloro-2-fluoro-phenyl)-5-vinyl-pyridine

To a stirred solution of1-[4-chloro-6-(5-chloro-2-fluoro-phenyl)-3-pyridyl]ethanol (1.2 g, 4.193mmol) in o-Xylene (10 mL) was added p-toluenesulfonic acid monohydrate(80 mg, 0.419 mmol) and hydroquinone (46 mg, 0.419 mmol). The reactionmixture was heated at 160° C. in a Dean-Stark apparatus for 48 h. Theprogress of reaction was monitored by TLC. After completion of thereaction, the mixture was concentrated under reduced pressure to removeo-Xylene. To the residue was added water (50 mL) and product wasextracted with EtOAc (2×50 mL). The combined organic layer was againwashed with water (40 mL) and brine solution (40 mL). The organic layerwas separated, dried over anhydrous sodium sulfate and concentratedunder reduced pressure to afford crude product which was purified byCombiFlash® chromatography using 0.5% EtOAc-hexane system as eluent toafford 4-chloro-2-(5-chloro-2-fluoro-phenyl)-5-vinyl-pyridine (270 mg)as a light yellow solid.

Step 6: Synthesis of methyl4-[[2-(5-chloro-2-fluoro-phenyl)-5-vinyl-4-pyridyl]amino]pyridine-3-carboxylate

To a mixture of 4-chloro-2-(5-chloro-2-fluoro-phenyl)-5-vinyl-pyridine(270 mg, 1.007 mmol), methyl 4-aminopyridine-3-carboxylate (169 mg,1.107 mmol) and potassium phosphate (tribasic) (428 mg, 2.014 mmol) in1,4-dioxane (10 mL) was purged with nitrogen gas for 30 min. To thisreaction mixture was added tris(dibenzylidineacetone)dipalladium(0) (92mg, 0.100 mmol) and Xantphos (87 mg, 0.151 mmol) and then the reactionmixture was purged with nitrogen for another 5 min. Then, the reactionmixture was heated at 100° C. overnight. The progress of reaction wasmonitored by TLC and LCMS. After completion of reaction, reactionmixture was diluted with EtOAc (50 mL) and filtered through a celitebed. The filtrate was washed with water (20 mL) and finally with brinesolution (20 mL). The organic layer was separated, dried over anhydroussodium sulfate and concentrated under reduced pressure to afford crudeproduct which was purified by CombiFlash® chromatography using 20%EtOAc-hexane system as eluent to afford methyl4-[[2-(5-chloro-2-fluoro-phenyl)-5-vinyl-4-pyridyl]amino]pyridine-3-carboxylate(100 mg) as an off-white solid.

Step 7: Synthesis of(S)-4-(2-(5-chloro-2-fluorophenyl)-5-vinylpyridin-4-ylamino)-N-(2-hydroxypropyl)nicotinamide

To a stirred solution of (S)-1-amino-propan-2-ol (14 mg, 0.187 mmol) inDCM (2 mL) was added potassium tert-butoxide (21 mg, 0.187 mmol) undernitrogen atmosphere at 0° C. The reaction mixture was stirred at RT for15 min. Then, to this reaction mixture was added a solution of methyl4-[[2-(5-chloro-2-fluoro-phenyl)-5-vinyl-4-pyridyl]amino]pyridine-3-carboxylate(60 mg, 0.156 mmol) in DCM (3 mL) dropwise. The reaction mixture washeated at 55° C. for 1 h. The progress of reaction was monitored by TLC.After completion of reaction, the mixture was diluted with DCM (15 mL).The organic layer washed with saturated solution of sodium bicarbonatesolution (10 mL), water (10 mL) and finally with brine solution (10 mL).The organic layer was separated, dried over anhydrous sodium sulfate andconcentrated under reduced pressure to obtain the crude product whichwas purified by reverse phase preparative HPLC to afford(S)-4-(2-(5-chloro-2-fluorophenyl)-5-vinylpyridin-4-ylamino)-N-(2-hydroxypropyl)nicotinamide (2 mg) as an off-white solid. The (R) enantiomer canbe synthesized utilizing (R)-1-aminopropan-2-ol in this step.

NMR: ¹H NMR (400 MHz, CD₃OD) δ (ppm): 8.76 (d, J=6.6 Hz, 2H), 8.35 (s,1H), 7.94 (dd, J=6.7, 2.8 Hz, 1H), 7.84 (s, 1H), 7.51-7.37 (m, 2H), 7.26(dd, J=10.7, 8.8 Hz, 1H), 6.92 (dd, J=17.6, 11.2 Hz, 2H), 5.98 (d,J=17.5 Hz, 1H), 5.60 (d, J=11.3 Hz, 1H), 3.97 (p, J=6.5 Hz, 1H), 3.56(dd, J=10.7, 5.5 Hz, 1H), 3.44 (dd, J=13.6, 4.6 Hz, 1H), 1.22 (d, J=6.4Hz, 3H). LCMS: 427.0 (M+1).

Example 11. Preparation of Compound Nos. 11, 11a and 11b Synthesis of(S)-4-(2-(5-chloro-2-fluorophenyl)-5-ethylpyridin-4-ylamino)-N-(2-hydroxypropyl)nicotinamide

Step 1: Synthesis of (4,6-dichloro-3-pyridyl)methanol

To a solution of methyl 4,6-dichloropyridine-3-carboxylate (1 g, 4.854mmol) in anhydrous THF (25 mL) was added a 1 M solution ofdiisobutylaluminium hydride in toluene (14.5 mL, 14.5 mmol) dropwiseunder nitrogen atmosphere at −78° C. The reaction mixture was stirredfor 2 h during which the reaction mixture slowly warmed to 0° C. Theprogress of reaction was monitored by TLC. After completion of reaction,the mixture was quenched with saturated ammonium chloride solution (20mL). EtOAc (100 mL) was added to the reaction mixture and filtered. Thefiltrate was washed with water (30 mL) followed by brine wash (30 mL).The organic layer was separated, dried over anhydrous sodium sulfate andconcentrated under reduced pressure to afford(4,6-dichloro-3-pyridyl)methanol (820 mg) as a white solid.

Step 2: Synthesis of 4,6-dichloropyridine-3-carbaldehyde

A solution of oxalyl chloride (2.32 mL, 26.963 mmol) in DCM (30 mL) wascooled to −78° C. To this solution was added DMSO (3.83 mL, 53.922 mmol)dropwise under nitrogen atmosphere. The reaction mixture was stirred atthe same temperature for another 30 min. To this reaction mixture wasadded a solution of (4,6-dichloro-3-pyridyl)methanol (1.6 g, 8.987 mmol)in DCM (10 mL) and then the reaction mixture was stirred for 30 min.Then, to this stirred reaction mixture was added triethylamine (11.2 mL,80.883 mmol). The reaction mixture was stirred at the same temperaturefor another 30 min. The progress of reaction was monitored by TLC. Aftercompletion of reaction, the mixture was quenched with saturated sodiumbicarbonate solution (30 mL). The product was extracted using DCM (2×50mL). The combined organic layer was washed with water (3×30 mL) andfinally with brine solution (30 mL). The organic layer was separated,dried over anhydrous sodium sulfate and concentrated under reducedpressure to afford 4,6-dichloropyridine-3-carbaldehyde (1.53 g) as alight yellow solid.

Step 3: Synthesis of 1-(4,6-dichloro-3-pyridyl)ethanol

To a solution of 4,6-dichloropyridine-3-carbaldehyde (1.53 g, 8.693mmol) in anhydrous THF (15 mL) was added a 3M solution ofmethylmagnesium bromide in diethyl ether (5.8 mL, 17.386 mmol) dropwiseunder nitrogen atmosphere at −78° C. The reaction mixture was stirredfor 1 h during which the reaction mixture slowly warmed to 0° C. Theprogress of reaction was monitored by TLC. After completion of reaction,the mixture was quenched with saturated ammonium chloride solution (15mL). The product was extracted using EtOAc (2×25 mL). The combinedorganic layer was washed with water (20 mL) and finally with brinesolution (20 mL). The organic layer was separated, dried over anhydroussodium sulfate and concentrated under reduced pressure to afford1-(4,6-dichloro-3-pyridyl)ethanol (1.56 g) as a light brown liquid.

Step 4: Synthesis of1-[4-chloro-6-(5-chloro-2-fluoro-phenyl)-3-pyridyl]ethanol

To a mixture of 1-(4,6-dichloro-3-pyridyl)ethanol (1.56 g, 8.123 mmol).(5-chloro-2-fluoro-phenyl)boronic acid (2.12 g, 12.184 mmol) and sodiumbicarbonate (1.36 g, 16.246 mmol) in 2:1 mixture of DMF:H₂O (21 mL) waspurged with nitrogen gas for 40 min. To this reaction mixture was addedbis(triphenylphosphine)palladium(II) dichloride (285 mg, 0.406 mmol) andto the reaction mixture was purged with nitrogen gas for another 5 min.The reaction mixture was then heated at 100° C. overnight. The progressof reaction was monitored by TLC and LCMS. After completion of reaction,water (20 mL) was added to the reaction mixture and product wasextracted with EtOAc (2×25 mL). The combined organic layer was washedwith water (3×25 mL) and finally with brine solution (25 mL). Theorganic layer was separated, dried over anhydrous sodium sulfate andconcentrated under reduced pressure to afford crude product which waspurified by column chromatography on silica gel (100-200 mesh) using 6%EtOAc:Hexane system as eluent to afford1-[4-chloro-6-(5-chloro-2-fluoro-phenyl)-3-pyridyl]ethanol (1.2 g) as alight brown liquid.

Step 5: Synthesis of4-chloro-2-(5-chloro-2-fluoro-phenyl)-5-vinyl-pyridine

To a stirred solution of1-[4-chloro-6-(5-chloro-2-fluoro-phenyl)-3-pyridyl]ethanol (1.2 g, 4.193mmol) in o-Xylene (10 mL) was added p-toluenesulfonic acid monohydrate(80 mg, 0.419 mmol) and hydroquinone (46 mg, 0.419 mmol). The reactionmixture was heated at 160° C. in a Dean-Stark apparatus for 48 h. Theprogress of reaction was monitored by TLC. After completion of reaction,the mixture was concentrated under reduced pressure to remove o-Xylene.To the residue was added water (50 mL) and product was extracted withEtOAc (2×50 mL). The combined organic layer was washed with water (40mL) and brine solution (40 mL). The organic layer was separated, driedover anhydrous sodium sulfate and concentrated under reduced pressure toafford crude product which was purified by CombiFlash® chromatographyusing 0.5% EtOAc-hexane system as eluent to afford4-chloro-2-(5-chloro-2-fluoro-phenyl)-5-vinyl-pyridine (270 mg) as alight yellow solid.

Step 6: Synthesis of methyl4-[[2-(5-chloro-2-fluoro-phenyl)-5-vinyl-4-pyridyl]amino]pyridine-3-carboxylate

To a mixture of 4-chloro-2-(5-chloro-2-fluoro-phenyl)-5-vinyl-pyridine(270 mg, 1.007 mmol), methyl 4-aminopyridine-3-carboxylate (169 mg,1.107 mmol) and potassium phosphate (tribasic) (428 mg, 2.014 mmol) in1,4-dioxane (10 mL) was purged with nitrogen gas for 30 min. To thisreaction mixture was added tris(dibenzylidineacetone)dipalladium(0) (92mg, 0.100 mmol) and Xantphos (87 mg, 0.151 mmol) and the reactionmixture was purged with nitrogen gas for another 5 min. The reactionmixture was then heated at 100° C. overnight. The progress of reactionwas monitored by TLC and LCMS. After completion of reaction, the mixturewas diluted with EtOAc (50 mL) and filtered through a celite bed. Thefiltrate was washed with water (20 mL) and finally with brine solution(20 mL). The organic layer was separated, dried over anhydrous sodiumsulfate and concentrated under reduced pressure to afford crude productwhich was purified by CombiFlash® chromatography using 20% EtOAc-hexanesystem as eluent to afford methyl4-[[2-(5-chloro-2-fluoro-phenyl)-5-vinyl-4-pyridyl]amino]pyridine-3-carboxylate(100 mg) as an off-white solid.

Step 7: Synthesis of methyl4-[[2-(5-chloro-2-fluoro-phenyl)-5-ethyl-4-pyridyl]amino]pyridine-3-carboxylate

To a stirred solution of4-[[2-(5-chloro-2-fluoro-phenyl)-5-vinyl-4-pyridyl]amino]pyridine-3-carboxylate(70 mg, 0.182 mmol) in a 1:1 mixture of EtOAc:EtOH (6 mL) was addedplatinum dioxide (30 mg). The reaction mixture was agitated underhydrogen atmosphere using hydrogen bladder at RT overnight. The progressof reaction was monitored by ¹H NMR. After completion of reaction,reaction mixture was filtered through a celite bed and filtrate wasconcentrated under reduced pressure to afford methyl4-[[2-(5-chloro-2-fluoro-phenyl)-5-ethyl-4-pyridyl]amino]pyridine-3-carboxylate(65 mg) as an off-white solid.

Step 8: Synthesis of(S)-4-(2-(5-chloro-2-fluorophenyl)-5-ethylpyridin-4-ylamino)-N-(2-hydroxypropyl)nicotinamide

To a stirred solution of methyl4-[[2-(5-chloro-2-fluoro-phenyl)-5-ethyl-4-pyridyl]amino]pyridine-3-carboxylate(65 mg, 0.168 mmol) and (S)-1-amino-propan-2-ol (19 mg, 0.252 mmol) intoluene (6 mL) was added a 1 M solution of trimethylaluminium in heptane(0.67 mL, 0.67 mmol) at RT. The reaction mixture was heated at refluxfor 2 h. The progress of reaction was monitored by TLC. After completionof reaction, reaction mixture was diluted with EtOAc (20 mL) and washedwith saturated solution of sodium bicarbonate (15 mL), water (10 mL)followed by brine wash (10 mL). The organic layer was separated, driedover anhydrous sodium sulfate and concentrated under reduced pressure toobtain the crude product which was purified by reverse phase preparativeHPLC to afford(S)-4-(2-(5-chloro-2-fluorophenyl)-5-ethylpyridin-4-ylamino)-N-(2-hydroxypropyl)nicotinamide (12 mg) as an off-white solid. The (R) enantiomercan be synthesized utilizing (R)-1-aminopropan-2-ol in this step.

NMR: ¹H NMR (400 MHz, CD₃OD) δ (ppm): 8.76 (s, 1H), 8.46 (s, 1H),8.37-8.25 (m, 1H), 7.84 (dd, J=6.7, 2.8 Hz, 1H), 7.76 (s, 1H), 7.52-7.35(m, 2H), 7.23 (dd, J=10.7, 8.8 Hz, 1H), 4.00 (td, J=6.8, 4.7 Hz, 1H),3.50-3.33 (m, 2H), 2.77 (q, J=7.5 Hz, 2H), 1.32 (t, J=7.5 Hz, 3H), 1.22(d, J=6.3 Hz, 3H). LCMS: 429.3 (M+1).

Example 12. Preparation of Compound Nos. 12, 12a and 12b Synthesis of(S)-4-(2-(5-chloro-2-fluorophenyl)-5-isopropylpyridin-4-ylamino)-N-(2-hydroxypropyl)pyrimidine-5-carboxamide

Steps 1 to 6 are the same as in Example 4.

Step 7: Synthesis of(S)-4-(2-(5-chloro-2-fluorophenyl)-5-isopropylpyridin-4-ylamino)-N-(2-hydroxypropyl)pyrimidine-5-carboxamide

To a stirred solution of(S)-4-(2-(5-chloro-2-fluorophenyl)-5-(prop-1-en-2-yl)pyridin-4-ylamino)-N-(2-hydroxypropyl)pyrimidine-5-carboxamide(120 mg, 0.271 mmol) in EtOAc (4 mL) was added platinum oxide (20 mg).The reaction mixture was stirred under hydrogen atmosphere usinghydrogen bladder at RT for 3 h. The progress of reaction was monitoredby LCMS. After completion of the reaction, the mixture was diluted withEtOAc (20 mL) and filtered through a celite bed. The filtrate wasconcentrated under reduced pressure to obtain the crude product whichwas purified by reverse phase preparative HPLC to afford(S)-4-(2-(5-chloro-2-fluorophenyl)-5-isopropylpyridin-4-ylamino)-N-(2-hydroxypropyl)pyrimidine-5-carboxamide(36 mg) TFA salt as a white solid. The (R) enantiomer can be synthesizedutilizing (R)-1-aminopropan-2-ol in this step.

NMR: ¹H NMR (400 MHz, CD₃OD) δ (ppm): 9.64 (s, 1H), 9.13 (s, 1H), 9.04(s, 1H), 8.52 (s, 1H), 7.86 (dd, J=6.3, 2.7 Hz, 1H), 7.73 (ddd, J=8.9,4.3, 2.6 Hz, 1H), 7.46 (t, J=9.5 Hz, 1H), 4.02 (td, J=6.8, 4.6 Hz, 1H),3.47 (m, 3H), 1.59-1.48 (d, J=8.0 Hz, 6H), 1.24 (d, J=6.3 Hz, 3H). LCMS:443.8 (M+1).

Example 13. Preparation of Compound Nos. 13, 13a and 13b Synthesis of4-[[2-(5-chloro-2-fluoro-phenyl)-5-methoxy-4-pyridyl]amino]-N-[(2S)-2-hydroxypropyl]pyridine-3-carboxamide

Step 1: Synthesis of 2-chloro-5-(methoxymethoxy)pyridine

To a solution of 6-chloropyridin-3-ol (2 g, 15.439 mmol) in DMF (10 mL)was added NaH (0.960 g, 23.200 mmol) under nitrogen atmosphere at 0° C.The reaction mixture was stirred at 0° C. for 30 min. Then, to thisreaction mixture was added a solution of chloro(methoxy)methane (1.62 g,20.121 mmol) in DMF (2 mL) dropwise. This reaction mixture was stirredat 0° C. for 30 min. The progress of reaction was monitored by TLC.After completion reaction, the mixture was quenched with ice-cold water(20 mL), extracted with EtOAc (2×50 mL). The combined organic layer waswashed with water (2×75 mL) and brine (75 mL), dried over anhydroussodium sulfate and concentrated under reduced pressure to afford2-chloro-5-(methoxymethoxy)pyridine (2.8 g) as a brown liquid.

Step 2: Synthesis of 2-chloro-4-iodo-5-(methoxymethoxy)pyridine

To a solution of 2-chloro-5-(methoxymethoxy)pyridine (2.1 g, 12.096mmol) in THF (20 mL) was added a 1.6 M solution of n-BuLi in hexane (8.3mL) under nitrogen atmosphere at −78° C. dropwise. The reaction mixturewas stirred at −78° C. for 1 h. Then, to this reaction mixture was addeda solution of iodine (3.6 g, 14.184 mmol) in THF (5 mL) dropwise. Thereaction mixture was stirred at −78° C. for 15 min. The progress ofreaction was monitored by TLC. After completion of the reaction, themixture was quenched with a saturated aqueous solution of NH₄Cl (50 mL)and saturated aqueous solution of Na₂S₂O₃ (50 mL), and the product wasextracted with EtOAc (2×150 mL). The combined organic layer was driedover anhydrous sodium sulfate and concentrated under reduced pressure toafford 2-chloro-4-iodo-5-(methoxymethoxy)pyridine (4 g) as a yellowsolid.

Step 3: Synthesis of 6-chloro-4-iodo-pyridin-3-ol

A mixture of solution of 2-chloro-4-iodo-5-(methoxymethoxy)pyridine (4.4g, 14.691 mmol) in THF (50 mL) and 3 N aqueous HCl (50 mL) was heated at60° C. for 2 h. The progress of reaction was monitored by TLC. Aftercompletion of the reaction, the mixture was basified using saturatedaqueous solution of NaHCO₃ (200 mL) and extracted with EtOAc (3×200 mL).The combined organic layer was dried over anhydrous sodium sulfate andconcentrated under reduced pressure to afford6-chloro-4-iodo-pyridin-3-ol (3.7 g) as a yellow solid.

Step 4: Synthesis of 2-chloro-4-iodo-5-methoxy-pyridine

To a solution of 6-chloro-4-iodo-pyridin-3-ol (300 mg, 1.174 mmol) inDMF (5 mL) was added methyl iodide (0.1 mL, 1.606 mmol) and K₂CO₃ (325mg, 2.351 mmol). The reaction mixture was stirred at RT for 2 h. Theprogress of reaction was monitored by TLC. After completion of thereaction, the mixture was diluted with water (20 mL) and extracted withEtOAc (2×50 mL). The combined organic layer was washed with water (2×75mL) and brine (50 mL), dried over anhydrous sodium sulfate andconcentrated under reduced pressure to afford2-chloro-4-iodo-5-methoxy-pyridine (250 mg) as a white solid.

Step 5: Synthesis of 4-aminopyridine-3-carboxylic acid

A solution of 4-chloropyridine-3-carboxylic acid (15 g, 0.095 mol) inaqueous NH₃ (600 mL) was heated in a pressure vessel at 150° C.overnight. The progress of reaction was monitored by TLC. Aftercompletion of reaction, the mixture was concentrated under reducedpressure. To this reaction mixture was added toluene (2×100 mL) toobtain 4-aminopyridine-3-carboxylic acid (17 g) as a white solid.

Step 6: Synthesis of methyl 4-aminopyridine-3-carboxylate

To a solution of 4-aminopyridine-3-carboxylic acid (17 g, 0.123 mol) inMeOH (300 mL) was added H₂SO₄ (45 mL) dropwise at 0° C. The reactionmixture was heated to reflux at 85° C. overnight. The progress ofreaction was monitored by TLC. After completion of the reaction, themixture was concentrated under reduced pressure to remove MeOH, residuewas basified with a saturated aqueous solution of Na₂CO₃ (400 mL),extracted with EtOAc (3×500 mL). The combined organic layer was driedover anhydrous sodium sulfate and concentrated under reduced pressure toafford methyl 4-aminopyridine-3-carboxylate (10.3 g) as a white solid.

Step 7: Synthesis of methyl 4-aminopyridine-3-carboxylate

To a mixture of 2-chloro-4-iodo-5-methoxy-pyridine (5 g, 0.0185 mol),methyl 4-aminopyridine-3-carboxylate (2.26 g, 0.0148 mol) and K₃PO₄(7.88 g, 0.0371 mol) in dioxane (200 mL) was purged with nitrogen for 20min. To this reaction mixture was added Pd₂(dba)₃ (1.7 g, 0.0018 mol)and Xantphos (2.15 G, 0.0037 mol) and the reaction mixture was purgedwith nitrogen gas for 5 min. The reaction mixture was heated at refluxovernight at 110° C. The progress of reaction was monitored by TLC.After completion of reaction, the mixture was diluted with water (250mL) and extracted with EtOAc (3×400 mL). The combined organic layer wasdried over anhydrous sodium sulfate and concentrated under reducedpressure to afford crude product. The crude product was purified bycolumn chromatography on silica gel (100-200 mesh) using 70%EtOAc-hexane system as eluent to obtain methyl4-aminopyridine-3-carboxylate (400 mg) as a yellow solid.

Step 8: Synthesis of 2(5-chloro-2-fluoro-phenyl)boronic acid

To a solution of 2-bromo-4-chloro-1-fluoro-benzene (25 g, 0.122 mol) indry diethyl ether (250 mL) was added n-BuLi (2.5 M in hexane, 53 mL) wasadded dropwise at −70° C. under nitrogen atmosphere. The reactionmixture was stirred at the same temperature for 30 min, followed by slowaddition of triisopropyl borate (30.3 mL, 0.134 mol). The reactionmixture turned to a white slurry, which was further stirred for 30 minat the same temperature. Then, the reaction mixture was warmed to RT andstirred for 1 h. The progress of reaction was monitored by TLC. Aftercompletion of reaction, the mixture was cooled to 0° C., quenched withaqueous 6 N HCl (400 mL), stirred at RT for 1 h and extracted with EtOAc(2×500 mL). The combined organic layer was dried over anhydrous sodiumsulfate and concentrated under reduced pressure to obtain the crudeproduct. The crude product was purified by washing with pentane toafford 2(5-chloro-2-fluoro-phenyl)boronic acid (19.5 g) as a whitesolid.

Step 9: Synthesis of methyl4-[[2-(5-chloro-2-fluoro-phenyl)-5-methoxy-4-pyridyl]amino]pyridine-3-carboxylate

A solution of methyl4-[(2-chloro-5-methoxy-4-pyridyl)amino]pyridine-3-carboxylate (360 mg,1.225 mmol), (5-chloro-2-fluoro-phenyl)boronic acid (853 mg, 4.902 mmol)and triethylamine (0.85 mL, 6.106 mmol) in toluene (25 mL) was purgedwith nitrogen for 20 min. To this reaction mixture was added tetrakis(142 mg, 0.122 mmol) and then again the reaction mixture was purged for5 min with nitrogen. The reaction mixture was heated at 100° C. for 12h. The progress of reaction was monitored by TLC. After completion ofreaction, the mixture was diluted with water (50 mL) and extracted withEtOAc (2×100 mL). The combined organic layer was dried over anhydroussodium sulfate and concentrated under reduced pressure to afford a crudeproduct. The crude product was purified by column chromatography onsilica gel (230-400 mesh) using 40% acetone-hexane system as eluent toobtain methyl4-[[2-(5-chloro-2-fluoro-phenyl)-5-methoxy-4-pyridyl]amino]pyridine-3-carboxylate(100 mg) as a brown solid.

Step 10: Synthesis of4-[[2-(5-chloro-2-fluoro-phenyl)-5-methoxy-4-pyridyl]amino]-N-[(2S)-2-hydroxypropyl]pyridine-3-carboxamide

A solution of (S)-1-aminopropan-2-ol (48 mg, 0.639 mmol) and potassiumtert-butoxide (46 mg, 0.410 mmol) in DCM (3 mL) was stirred at RT for 30min. To this stirred reaction mixture was added a solution of methyl4-[[2-(5-chloro-2-fluoro-phenyl)-5-methoxy-4-pyridyl]amino]pyridine-3-carboxylate(100 mg, 0.258 mmol) in DCM (3 mL). The reaction mixture was heated at50° C. for 2 h. The progress of reaction was monitored by TLC. Aftercompletion of reaction, reaction mixture was diluted with water (25 mL)and extracted with EtOAc (3×100 mL). The combined organic layer wasdried over anhydrous sodium sulfate and concentrated under reducedpressure to afford a crude product. The crude product was purified byreverse phase CombiFlash® using 50% MeOH in 0.05% aqueous TFA as eluentto obtain4-[[2-(5-chloro-2-fluoro-phenyl)-5-methoxy-4-pyridyl]amino]-N-[(2S)-2-hydroxypropyl]pyridine-3-carboxamide(20 mg) TFA salt as a white solid. The (R) enantiomer can be synthesizedutilizing (R)-1-aminopropan-2-ol in this step.

NMR: ¹H NMR (400 MHz, CD₃OD) δ (ppm): 8.90 (s, 1H), 8.58 (s, 1H), 8.41(s, 1H), 8.03-7.86 (m, 2H), 7.55 (d, J=6.7 Hz, 1H), 7.47 (ddd, J=8.8,4.2, 2.6 Hz, 1H), 7.27 (dd, J=10.7, 8.8 Hz, 1H), 4.12 (s, 3H), 4.00 (pd,J=6.4, 4.2 Hz, 1H), 3.48 (m, 2H), 3.40-3.33 (m, 1H), 1.24 (d, J=6.2 Hz,3H).

Example 14. Preparation of Compound No. 14 Synthesis ofN-(2-acetamidoethyl)-4-[[2-(5-chloro-2-fluoro-phenyl)-5-isopropyl-4-pyridyl]amino]pyridine-3-carboxamide

Steps 1 to 8 are the same as in Comparative Example 1

Step 9: Synthesis ofN-(2-acetamidoethyl)-4-[[2-(5-chloro-2-fluoro-phenyl)-5-isopropyl-4-pyridyl]amino]pyridine-3-carboxamide

To a solution of4-[[2-(5-chloro-2-fluoro-phenyl)-5-isopropyl-4-pyridyl]amino]pyridine-3-carboxylicacid (200 mg, 0.518 mmol) in DMF (7 mL) was added N,N-diisopropylethylamine (0.45 mL, 2.59 mmol) and HATU (317 mg, 0.829 mmol) and thereaction mixture was stirred at RT for 15 min under nitrogen atmosphere.To the reaction mixture was added a solution ofN-(2-aminoethyl)acetamide (132 mg, 1.295 mmol) in DMF (3 mL) and thereaction mixture was stirred at RT overnight. The progress of reactionwas monitored by TLC. After completion of the reaction, the mixture wasdiluted with water and extracted with EtOAc (50 mL). The organic layerwas washed with water (2×10 mL) and brine solution (10 mL), dried overanhydrous sodium sulfate and concentrated under reduced pressure toobtain the crude product. The crude product was purified by reversephase HPLC to affordN-(2-acetamidoethyl)-4-[[2-(5-chloro-2-fluoro-phenyl)-5-isopropyl-4-pyridyl]amino]pyridine-3-carboxamide(19 mg).

NMR: ¹H NMR (400 MHz, CD₃OD) δ (ppm): 8.72 (s, 1H), 8.59 (s, 1H), 8.32(d, J=6.0 Hz, 1H), 7.89 (dd, J=6.7, 2.7 Hz, 1H), 7.80 (s, 1H), 7.45(ddd, J=8.8, 4.3, 2.8 Hz, 1H), 7.37 (d, J=6.0 Hz, 1H), 7.25 (dd, J=10.7,8.8 Hz, 1H), 3.52 (dd, J=6.7, 5.1 Hz, 2H), 3.42 (t, J=5.9 Hz, 2H),3.30-3.18 (m, 1H), 1.94 (s, 3H), 1.41 (d, J=6.9 Hz, 6H).

Example 15. Preparation of Compound No. 15 Synthesis ofN-(2-amino-2-oxo-ethyl)-4-[[2-(5-chloro-2-fluoro-phenyl)-5-isopropyl-4-pyridyl]amino]pyridine-3-carboxamide

Steps 1 to 8 are the same as in Comparative Example 1

Step 9: Synthesis ofN-(2-amino-2-oxo-ethyl)-4-[[2-(5-chloro-2-fluoro-phenyl)-5-isopropyl-4-pyridyl]amino]pyridine-3-carboxamide

To a solution of4-[[2-(5-chloro-2-fluoro-phenyl)-5-isopropyl-4-pyridyl]amino]pyridine-3-carboxylicacid (200 mg, 0.518 mmol) in a 10:1 mixture of DCM:DMF (10 mL) was addedN,N-diisopropylethyl amine (0.45 mL, 2.59 mmol) and HATU (317 mg, 0.829mmol) and the reaction mixture was stirred at RT for 15 min undernitrogen atmosphere. To this stirred reaction mixture was added2-aminoacetamide hydrochloride (143 mg, 1.295 mmol) the reaction mixturewas again stirred at RT overnight. The progress of reaction wasmonitored by TLC. After completion of reaction, the mixture was dilutedwith water and extracted with EtOAc (50 mL). The organic layer waswashed with water (2×10 mL) and brine solution (10 mL), dried overanhydrous sodium sulfate and concentrated under reduced pressure toobtain the crude product. The crude product was purified by reversephase HPLC to affordN-(2-amino-2-oxo-ethyl)-4-[[2-(5-chloro-2-fluoro-phenyl)-5-isopropyl-4-pyridyl]amino]pyridine-3-carboxamide(115 mg) as a white solid.

NMR: ¹H NMR (400 MHz, DMSO-d6) δ (ppm): 10.67 (s, 1H), 9.14 (t, J=5.9Hz, 1H), 8.87 (s, 1H), 8.64 (s, 1H), 8.36 (d, J=5.9 Hz, 1H), 7.99 (dd,J=6.7, 2.8 Hz, 1H), 7.78 (d, J=1.4 Hz, 1H), 7.58-7.45 (m, 2H), 7.45-7.26(m, 2H), 7.09 (s, 1H), 3.85 (d, J=5.9 Hz, 2H), 3.14 (m, 1H), 1.32 (d,J=6.8 Hz, 6H).

Example 16. Preparation of Compound Nos. 16, 16a and 16b Synthesis of(S)-4-(2-(5-chloro-2-fluorophenyl)-5-(dimethylamino)pyridin-4-ylamino)-N-(2-hydroxypropyl)nicotinamide

Step 1: Synthesis of 4,6-dichloropyridine-3-carboxylic acid

To a stirred solution of methyl 4,6-dichloropyridine-3-carboxylate (3.5g, 16.990 mmol) in THF (30 mL) was added a solution of lithium hydroxidemonohydrate (3.56 g, 84.951 mmol) in water (15 mL). The reaction mixturewas stirred at RT for 1.5 h. The progress of reaction was monitored byTLC. After completion of reaction, the pH of the aqueous layer wasadjusted to 2 by the addition of 2 N HCl (aq.) and the product wasextracted with EtOAc (2×50 mL). The organic layer was separated, driedover anhydrous sodium sulfate and concentrated under reduced pressure toafford 4,6-dichloropyridine-3-carboxylic acid (3.2 g) as a white solid.

Step 2: Synthesis of tert-butyl N-(4,6-dichloro-3-pyridyl)carbamate

To a solution of 4,6-dichloropyridine-3-carboxylic acid (2.8 g, 14.58mmol) in dry DMF (10 mL) was added triethylamine (2.24 mL, 16.04 mmol)at 0° C. followed by addition of diphenylphosphoryl azide (3.45 mL,16.04 mmol). The reaction mixture was stirred at RT for 1 h and pouredonto a mixture of ice-water-EtOAc. The product was extracted with EtOAc(2×50 mL). The combined extracts were washed with water (50 mL),saturated solution of sodium bicarbonate (50 mL) and finally with brinesolution (50 mL). The organic layer was separated, dried over anhydroussodium sulfate and concentrated under reduced pressure to afford lightyellow solid which was dissolved in dry toluene (30 mL) and heated toreflux for 2 h. Then the reaction mixture was cooled to RT and t-butanol(8.36 mL, 87.48 mmol) was added. The reaction mixture was heated at 90°C. for 4 h. The reaction was monitored by TLC. After completion, thereaction mixture was concentrated under reduced pressure, water wasadded to the residue and product was extracted with EtOAc (2×100 mL).Removal of EtOAc under reduced pressure afforded an oily residue thatwas purified by column chromatography on silica gel (100-200) mesh)using 1% EtOAc-hexane system as eluent to afford tert-butylN-(4,6-dichloro-3-pyridyl)carbamate (3.8 g) as a light yellow liquid.

Step 3: Synthesis of 4,6-dichloropyridin-3-amine

To a stirred solution of tert-butyl N-(4,6-dichloro-3-pyridyl)carbamate(3.8 g, 14.44 mmol) in DCM (15 mL) was added trifluoroacetic acid (5 mL)dropwise at 0° C. The reaction mixture was slowly warmed to RT andstirred for 3 h. The progress of reaction was monitored by TLC. Aftercompletion of reaction, the mixture was concentrated under reducedpressure. To the residue was added saturated solution of sodiumbicarbonate (30 mL) and product was extracted with EtOAc (100 mL). Theorganic layer was again washed with water (30 mL) and brine solution (30mL). The organic layer was separated, dried over anhydrous sodiumsulfate. Removal of EtOAc under reduced pressure afforded product whichwas again washed with n-pentane and dried to afford4,6-dichloropyridin-3-amine (1.9 g) as a light brown solid.

Step 4: Synthesis of 4,6-dichloro-N-methyl-pyridin-3-amine

To a stirred solution of 4,6-dichloropyridin-3-amine (1.42 g, 8.712mmol) in dry DMF (8 mL) was added a 60% suspension of sodium hydride inmineral oil (767 mg, 19.166 mmol) under nitrogen atmosphere at 0° C. Thereaction mixture was stirred at this temperature for 5-10 min. To thisstirred reaction mixture was added a solution of methyl iodide (1.2 mL,19.166 mmol) in dry DMF (2 mL) dropwise. Then, the reaction mixture wasstirred at RT for 20 min. The progress of reaction was monitored by TLC.After completion of the reaction, the mixture was quenched by additionof ice-water and product was extracted with EtOAc (50 mL). The organiclayer was again washed with water (2×20 mL) and brine solution (20 mL).The organic layer was separated, dried over anhydrous sodium sulfate andconcentrated under reduced pressure to afford4,6-dichloro-N-methyl-pyridin-3-amine (1.6 g) as a light brown solid.

Step 5: Synthesis of4-chloro-6-(5-chloro-2-fluoro-phenyl)-N,N-dimethyl-pyridin-3-amine

A mixture of 4,6-dichloro-N-methyl-pyridin-3-amine (1.6 g, 8.374 mmol),(5-chloro-2-fluoro-phenyl)boronic acid (2.19 g, 12.561 mmol) and sodiumbicarbonate (1.4 g, 16.748 mmol) in a 2:1 mixture DMF:H₂O (21 mL) waspurged with nitrogen gas for 40 min. To this reaction mixture was addedbis(triphenylphosphine)palladium(II) dichloride (294 mg, 0.418 mmol) andthe reaction mixture was purged with nitrogen gas for another 5 min.Then, the reaction mixture was heated at 100° C. overnight. The progressof reaction was monitored by TLC and LCMS. After completion of reaction,water (20 mL) was added to the reaction mixture and product wasextracted with EtOAc (2×25 mL). The combined organic layer was washedwith water (3×25 mL) and finally with brine solution (25 mL). Theorganic layer was separated, dried over anhydrous sodium sulfate andconcentrated under reduced pressure to afford4-chloro-6-(5-chloro-2-fluoro-phenyl)-N,N-dimethyl-pyridin-3-amine (1.2g) as an off-white solid.

Step 6: Synthesis of methyl4-[[2-(5-chloro-2-fluoro-phenyl)-5-(dimethylamino)-4-pyridyl]amino]pyridine-3-carboxylate

A mixture of4-chloro-6-(5-chloro-2-fluoro-phenyl)-N,N-dimethyl-pyridin-3-amine (980mg, 3.436 mmol), methyl 4-aminopyridine-3-carboxylate (272 mg, 1.787mmol) and potassium phosphate (tribasic) (693 mg, 3.264 mmol) in1,4-dioxane (20 mL) was purged with nitrogen gas for 30 min. To thisreaction mixture was added tris(dibenzylidineacetone)dipalladium(0) (151mg, 0.165 mmol) and Xantphos (139 mg, 0.240 mmol) and the reactionmixture was purged with nitrogen gas for another 5 min. The reactionmixture was then heated at 100° C. overnight. The progress of reactionwas monitored by TLC and LCMS. After completion of the reaction, themixture was diluted with EtOAc (50 mL) and filtered through a celitebed. The filtrate was washed with water (20 mL) and finally with brinesolution (20 mL). The organic layer was separated, dried over anhydroussodium sulfate and concentrated under reduced pressure to afford a crudeproduct which was purified by CombiFlash®® chromatography using 25%EtOAc-hexane system as eluent to afford methyl4-[[2-(5-chloro-2-fluoro-phenyl)-5-(dimethylamino)-4-pyridyl]amino]pyridine-3-carboxylate(98 mg) as an off-white solid.

Step 7: Synthesis of(S)-4-(2-(5-chloro-2-fluorophenyl)-5-(dimethylamino)pyridin-4-ylamino)-N-(2-hydroxypropyl)nicotinamide

To a stirred solution of methyl4-[[2-(5-chloro-2-fluoro-phenyl)-5-(dimethylamino)-4-pyridyl]amino]pyridine-3-carboxylate(98 mg, 0.244 mmol) and (S)-1-amino-propan-2-ol (28 mg, 0.366 mmol) intoluene (6 mL) was added a 1 M solution of trimethylaluminium in heptane(0.98 mL, 0.98 mmol) at RT. The reaction mixture was heated at refluxfor 4 h. The progress of reaction was monitored by TLC. After completionof the reaction, the mixture was diluted with EtOAc (30 mL) and washedwith saturated solution of sodium bicarbonate (15 mL), water (15 mL)followed by brine wash (15 mL). The organic layer was separated, driedover anhydrous sodium sulfate and concentrated under reduced pressure toobtain the crude product which was purified by CombiFlash®chromatography using 6% MeOH-DCM system as eluent to afford(S)-4-(2-(5-chloro-2-fluorophenyl)-5-(dimethylamino)pyridin-4-ylamino)-N-(2-hydroxypropyl)nicotinamide(30 mg) as an off-white solid. The (R) enantiomer can be synthesizedutilizing (R)-1-aminopropan-2-ol in this step.

NMR: ¹H NMR (400 MHz, CDCl₃) δ (ppm): 10.21 (s, 1H), 8.71 (s, 1H), 8.41(d, J=9.0 Hz, 2H), 7.99 (dd, J=6.8, 2.8 Hz, 1H), 7.78 (d, J=1.9 Hz, 1H),7.43 (d, J=5.9 Hz, 1H), 7.29 (ddd, J=8.5, 4.1, 2.6 Hz, 1H), 7.08 (dd,J=10.7, 8.7 Hz, 1H), 6.88 (bs, 1H), 4.14-4.02 (m, 1H), 3.72 (ddd,J=14.0, 6.7, 3.1 Hz, 1H), 3.30 (ddd, J=13.4, 8.0, 4.7 Hz, 1H), 2.85 (s,6H), 1.29 (d, J=6.3 Hz, 3H). LCMS: 444.2 (M+1).

Example 17. Preparation of Compound Nos. 17, 17a and 17b Synthesis of4-[[2-(5-chloro-2-fluoro-phenyl)-5-(1-methoxy-1-methyl-ethyl)-4-pyridyl]amino]-N-(2-hydroxypropyl)pyridine-3-carboxamide

Step 1: Synthesis of 2-(4,6-dichloro-3-pyridyl)propan-2-ol)

A solution of methyl 4,6-dichloropyridine-3-carboxylate (5 g, 0.0243mol) in dry THF (60 mL) was cooled to −60° C. under nitrogen atmosphere.To this reaction mixture was added methylmagnesium bromide (3 M in THF,28.3 mL). The reaction mixture was warmed to RT and stirred for 2 h. Theprogress of reaction was monitored by TLC. After completion of reaction,the mixture was cooled to 0° C. and quenched with saturated aqueousammonium chloride solution (200 mL) and extracted with EtOAc (2×300 mL).The organic layer was dried over anhydrous sodium sulfate andconcentrated under reduced pressure to afford2-(4,6-dichloro-3-pyridyl)propan-2-ol (4.91 g) as a yellow liquid.

Step 2: Synthesis of 2(5-chloro-2-fluoro-phenyl)boronic acid

1 To a solution of 2-bromo-4-chloro-1-fluoro-benzene (25 G, 0.122 mol)in dry diethyl ether (250 mL) was added n-BuLi (2.5 M in hexane, 53 mL)dropwise at −70° C. under nitrogen atmosphere. The reaction mixture wasstirred at the same temperature for 30 min, followed by slow addition oftriisopropyl borate (30.3 mL, 0.134 mol). Formation of a white slurrywas observed, which was stirred for 30 min at the same temperature.Then, the reaction mixture was warmed to RT and stirred for 1 h. Theprogress of reaction was monitored by TLC. After the completion of thereaction, the mixture was cooled to 0° C. and quenched with aqueous 6 NHCl (400 mL), stirred at RT for 1 h and then extracted with EtOAc (2×500mL). The organic layer was dried over anhydrous sodium sulfate andconcentrated under reduced pressure to obtain the crude product. Thecrude product was purified by washing with pentane to afford2(5-chloro-2-fluoro-phenyl)boronic acid (19.5 g) as a white solid.

Step 3: Synthesis of2-[4-chloro-6-(5-chloro-2-fluoro-phenyl)-3-pyridyl]propan-2-ol

A solution of methyl 2-(4,6-dichloro-3-pyridyl)propan-2-ol (800 mg,3.882 mmol), (5-chloro-2-fluoro-phenyl)boronic acid (1.150 g, 6.595mmol) in DMF (18 mL) was mixed with solution of NaHCO₃ (625 mg, 7.761mmol) in water (9 mL). The reaction mixture was purged with nitrogen for15 min followed by addition of palladium dichloro diphenyl phosphine(136 mg, 0.193 mmol). The reaction mixture was again purged for 5 minand heated at 100° C. overnight. The progress of reaction was monitoredby TLC. After completion of reaction, the mixture was diluted with water(60 mL) and extracted with EtOAc (3×125 mL). The organic layers werewashed with water (2×300 mL) and brine (150 mL), dried over anhydroussodium sulfate and concentrated under reduced pressure to afford a crudeproduct. The crude product was purified by CombiFlash® using 10%EtOAc-hexane system as eluent to obtain2-[4-chloro-6-(5-chloro-2-fluoro-phenyl)-3-pyridyl]propan-2-ol (750 mg)as a pale yellow sticky material.

Step 4: Synthesis of4-chloro-2-(5-chloro-2-fluoro-phenyl)-5-(1-methoxy-1-methyl-ethyl)pyridine

To a solution of2-[4-chloro-6-(5-chloro-2-fluoro-phenyl)-3-pyridyl]propan-2-ol (110 mg,0.366 mmol) in THF (5 mL) was added NaH (33 mg, 0.797 mmol) and MeI(0.03 mL, 0.481 mmol) at 0° C. under nitrogen atmosphere. The reactionmixture was warmed to RT and stirred overnight. The progress of reactionwas monitored by TLC. After completion of reaction, the mixture wasquenched with ice-cold water (10 mL) and extracted with EtOAc (2×15 mL).The organic layers were dried over anhydrous sodium sulfate andconcentrated under reduced pressure to afford4-chloro-2-(5-chloro-2-fluoro-phenyl)-5-(1-methoxy-1-methyl-ethyl)pyridine(100 mg) as a brown semisolid.

Step 5: Synthesis of 4-aminopyridine-3-carboxylic acid

A solution of 4-chloropyridine-3-carboxylic acid (15 g, 0.095 mol) inaqueous NH₃ (600 mL) was heated in a pressure vessel at 150° C.overnight. The progress of reaction was monitored by TLC. Aftercompletion of reaction, the mixture was concentrated under reducedpressure. To this reaction mixture was added toluene (2×100 mL) toobtain 4-aminopyridine-3-carboxylic acid (17 g) as a white solid.

Step 6: Synthesis of methyl 4-aminopyridine-3-carboxylate

To a solution of 4-aminopyridine-3-carboxylic acid (17 g, 0.123 mol) inMeOH (300 mL) was added H₂SO₄ (45 mL) dropwise at 0° C. The reactionmixture was heated to reflux at 85° C. overnight. The progress ofreaction was monitored by TLC. After completion of the reaction, themixture was concentrated under reduced pressure. The residue wasbasified with saturated aqueous Na₂CO₃ solution (400 mL), and extractedwith EtOAc (3×500 mL). The organic layers were dried over anhydroussodium sulfate and concentrated under reduced pressure to afford methyl4-aminopyridine-3-carboxylate (10.3 g) as a white solid.

Step 7: Synthesis of methyl4-[[2-(5-chloro-2-fluoro-phenyl)-5-(1-methoxy-1-methyl-ethyl)-4-pyridyl]amino]pyridine-3-carboxylate

A mixture of4-chloro-2-(5-chloro-2-fluoro-phenyl)-5-(1-methoxy-1-methyl-ethyl)pyridine(200 mg, 0.636 mmol), methyl 4-aminopyridine-3-carboxylate (107 mg,0.703 mmol) and K₃PO₄ (270 mg, 1.271 mmol) in dioxane (1.5 mL) waspurged with nitrogen for 10 min, followed by addition of Pd₂(dba)₃ (58mg, 0.063 m mol) and Xantphos (74 mg, 0.127 mmol) and again purged for 2min. The reaction mixture was heated in a microwave at 100° C. for 2 h.The progress of reaction was monitored by TLC and LCMS. After completionof reaction, the mixture was diluted with EtOAc (15 mL) and washed withwater (2×10 mL). The organic layer was dried over anhydrous sodiumsulfate and concentrated under reduced pressure to afford a crudeproduct. The crude product was purified by CombiFlash® using 25%EtOAc-hexane as eluent to obtain methyl4-[[2-(5-chloro-2-fluoro-phenyl)-5-(1-methoxy-1-methyl-ethyl)-4-pyridyl]amino]pyridine-3-carboxylate(42 mg).

Step 8: Synthesis of4-[[2-(5-chloro-2-fluoro-phenyl)-5-(1-methoxy-1-methyl-ethyl)-4-pyridyl]amino]pyridine-3-carboxylicacid

To a stirred solution of potassium tert-butoxide (21 mg, 0.197 mmol) inDCM (2 mL) was added a solution of methyl4-[[2-(5-chloro-2-fluoro-phenyl)-5-(1-methoxy-1-methyl-ethyl)-4-pyridyl]amino]pyridine-3-carboxylate(50 mg, 0.116 mmol) in DCM (2 mL). The reaction mixture was heated at50° C. for 4 h. The progress of reaction was monitored by TLC and LCMS.After completion of the reaction, the mixture was diluted with DCM (20mL) and washed with water (2×10 mL). The organic layer was dried overanhydrous sodium sulfate and concentrated under reduced pressure toobtain4-[[2-(5-chloro-2-fluoro-phenyl)-5-(1-methoxy-1-methyl-ethyl)-4-pyridyl]amino]pyridine-3-carboxylicacid (50 mg) as a yellow solid.

Step 9: Synthesis of4-[[2-(5-chloro-2-fluoro-phenyl)-5-(1-methoxy-1-methyl-ethyl)-4-pyridyl]amino]-N-(2-hydroxypropyl)pyridine-3-carboxamide

To a solution of4-[[2-(5-chloro-2-fluoro-phenyl)-5-(1-methoxy-1-methyl-ethyl)-4-pyridyl]amino]pyridine-3-carboxylicacid (50 mg, 0.120 mmol) in DMF (2 mL) was added HATU (91 mg, 0.289mmol) and DIPEA (0.13 mL, 0.746 mmol) at 0° C. under nitrogenatmosphere. The reaction mixture was stirred at 0° C. for 15 minfollowed by addition of (S)-1-aminopropan-2-ol (18 mg, 0.239 mmol) inDMF (1 mL). Then, the reaction mixture was warmed to RT and stirredovernight. The progress of reaction was monitored by TLC. Aftercompletion of the reaction, the mixture was diluted with EtOAc (25 mL)and washed with water (2×15 mL), saturated aqueous NaHCO₃ solution (15mL), saturated aqueous NH₄Cl solution (15 mL) and brine (15 mL). Theorganic layers were dried over anhydrous sodium sulfate and concentratedunder reduced pressure to obtain the crude product. The crude productwas purified by reverse phase preparative HPLC to obtain4-[[2-(5-chloro-2-fluoro-phenyl)-5-(1-methoxy-1-methyl-ethyl)-4-pyridyl]amino]-N-(2-hydroxypropyl)pyridine-3-carboxamide(19.8 mg) as a white solid. The (R) enantiomer can be synthesizedutilizing (R)-1-aminopropan-2-ol in this step.

NMR: ¹H NMR (400 MHz, CD₃OD) δ (ppm): 8.70 (s, 1H), 8.52 (s, 1H), 8.36(d, J=6.0 Hz, 1H), 7.89 (dd, J=6.7, 2.8 Hz, 1H), 7.83 (d, J=1.8 Hz.,1H), 7.53 (d, J=6.0 Hz, 1H), 7.46 (ddd, J=8.8, 4.3, 2.8 Hz, 1H), 7.25(dd, J=10.7, 8.8 Hz, 1H), 3.98 (td, J=6.7, 4.8 Hz, 1H), 3.44 (m, 2H),3.23 (s, 3H), 1.70 (s, 6H), 1.25 (d, J=6.2, 3H).

Example 18. Preparation of Compound No. 18 Synthesis of4-[[2-(5-chloro-2-fluoro-phenyl)-5-isopropyl-4-pyridyl]amino]-N-[2-(methanesulfonamido)ethyl]pyridine-3-carboxamide

Steps 1 to 8 are the same as in Comparative Example 1

Step 9: Synthesis of4-[[2-(5-chloro-2-fluoro-phenyl)-5-isopropyl-4-pyridyl]amino]-N-[2-(methanesulfonamido)ethyl]pyridine-3-carboxamide

To a solution of4-[[2-(5-chloro-2-fluoro-phenyl)-5-isopropyl-4-pyridyl]amino]pyridine-3-carboxylicacid (100 mg, 0.245 mmol) in DMF (4 mL) was added N,N-diisopropylethylamine (0.17 mL, 0.98 mmol) and HATU (149 mg, 0.39 mmol) and stirred atRT for 15 min under nitrogen atmosphere. Then, to this reaction mixturewas added N-(2-aminoethyl)methanesulfonamide hydrochloride (107 mg,0.613 mmol) and the reaction mixture was stirred at RT overnight. Theprogress of reaction was monitored by TLC. After completion of reaction,the mixture was diluted with water and extracted with EtOAc (50 mL). Theorganic layer was washed with water (2×10 mL) and brine solution (10mL), dried over anhydrous sodium sulfate and concentrated under reducedpressure to obtain the crude product. The crude product was purified byreverse phase HPLC to afford4-[[2-(5-chloro-2-fluoro-phenyl)-5-isopropyl-4-pyridyl]amino]-N-[2-(methanesulfonamido)ethyl]pyridine-3-carboxamide (25 mg) as a white solid.

NMR: ¹H NMR (400 MHz CD₃OD) δ (ppm): 8.76 (s, 1H), 8.57 (s, 1H), 8.31(d, J=5.9 Hz, 1H), 7.88 (dd, J=6.7, 2.7 Hz, 1H), 7.78 (s, 1H), 7.45(ddd, J=8.8, 4.2, 2.7 Hz, 1H), 7.36 (d, J=5.3 Hz, 1H), 7.25 (dd, J=10.7,8.8 Hz, 1H), 3.55 (d, J=6.0 Hz, 2H), 3.37-3.17 (m, 3H), 2.96 (s, 3H),1.40 (d, J=6.9 Hz; 6H).

Example 19. Preparation of Compound No. 19 Synthesis ofN-(2-aminoethyl)-4-[[2-(5-chloro-2-fluoro-phenyl)-5-isopropyl-4-pyridyl]amino]pyridine-3-carboxamide

Steps 1 to 8 are the same as in Comparative Example 1

Step 9: Synthesis of tert-butylN-[2-[[4-[[2-(5-chloro-2-fluoro-phenyl)-5-isopropyl-4-pyridyl]amino]pyridine-3-carbonyl]amino]ethyl]carbamate

To a solution of4-[[2-(5-chloro-2-fluoro-phenyl)-5-isopropyl-4-pyridyl]amino]pyridine-3-carboxylicacid (150 mg, 0.367 mmol) in DMF (4 mL) was add N,N-diisopropylethylamine (0.26 mL, 1.47 mmol) and HATU (224 mg, 0.588 mmol) and stirred atRT for 15 min under nitrogen atmosphere. Then, to this reaction mixturewas added tert-butyl N-(2-aminoethyl)carbamate hydrochloride (147 mg,0.919 mmol) and the reaction mixture was stirred at RT overnight. Theprogress of reaction was monitored by TLC. After completion of reaction,the mixture was diluted with water and extracted with EtOAc (50 mL). Theorganic layer was washed with water (2×10 mL) and brine solution (10mL), dried over anhydrous sodium sulfate and concentrated under reducedpressure to obtain the crude product. The crude product was purified bycolumn chromatography on silica gel (100:200 mesh) using 80%EtOAc-hexane system as eluent to afford tert-butylN-[2-[[4-[[2-(5-chloro-2-fluoro-phenyl)-5-isopropyl-4-pyridyl]amino]pyridine-3-carbonyl]amino]ethyl]carbamate(75 mg).

Step 10: Synthesis ofN-(2-aminoethyl)-4-[[2-(5-chloro-2-fluoro-phenyl)-5-isopropyl-4-pyridyl]amino]pyridine-3-carboxamide

To a stirred solution of tert-butylN-[2-[[4-[[2-(5-chloro-2-fluoro-phenyl)-5-isopropyl-4-pyridyl]amino]pyridine-3-carbonyl]amino]ethyl]carbamate(75 mg, 0.142 mmol) in DCM (4 mL) was added TFA (1.5 mL) and stirred atRT for 1 h. The progress of reaction was monitored by TLC and NMR. Aftercompletion of reaction, the mixture was concentrated under reducedpressure to obtain the crude product. The crude product was trituratedwith diethyl ether and dried to obtain a crude residue, which waspurified by reverse phase HPLC to affordN-(2-aminoethyl)-4-[[2-(5-chloro-2-fluoro-phenyl)-5-isopropyl-4-pyridyl]amino]pyridine-3-carboxamide(6 mg) as an off white solid.

NMR: ¹H NMR (400 MHz, CD₃OD) δ (ppm): 8.77 (s, 1H), 8.60 (s, 1H), 8.32(d, J=6.0 Hz, 1H), 7.90 (dt, J=6.7, 3.3 Hz, 1H), 7.80 (d, J=1.9 Hz, 1H),7.46 (ddd, J=8.8, 4.3, 2.6 Hz, 1H), 7.36 (d, J=6.1 Hz 1H), 7.25 (t,J=9.75 Hz, 1H), 3.65 (t, J=6.0 Hz, 2H), 3.12 (t, J=6.0 Hz, 2H), 1.40 (d,J=6.9 Hz, 6H).

Example 20. Preparation of Compound Nos. 20, 20a and 20b Synthesis of3-[[2-(5-chloro-2-fluoro-phenyl)-5-isopropenyl-4-pyridyl]amino]-N-(2-hydroxypropyl)-1H-pyrazole-4-carboxamide

To a solution of3-[[2-(5-chloro-2-fluoro-phenyl)-5-isopropenyl-4-pyridyl]amino]-1H-pyrazole-4-carboxylicacid (160 mg, 0.42 mmol) in DMF (4 mL) was added EDC.HCl (164 mg, 0.85mmol), HOBT (115 mg, 0.85 mmol) and followed by the addition of DIPEA(0.37 mL, 2.14 mmol). The reaction mixture was stirred at RT for 15 min.Then, to this reaction mixture was added a solution of(S)-1-aminopropan-2-ol (96 mg 1.28 mmol) in DMF (1 mL) and the reactionmixture was stirred at RT overnight. The progress of reaction wasmonitored by LCMS. After completion of the reaction, the mixture wasdiluted with water (15 mL) and the product was extracted with EtOAc(2×100 mL). The organic layers were washed with water (2×40 mL), driedover sodium sulfate and concentrated under reduced pressure to get thecrude product. The crude product was purified by preparative HPLC toafford(S)-3-[[2-(5-chloro-2-fluoro-phenyl)-5-isopropenyl-4-pyridyl]amino]-N-(2-hydroxypropyl)-1H-pyrazole-4-carboxamide(7.08 mg). The (R) enantiomer can be synthesized utilizing(R)-1-aminopropan-2-ol in this step.

NMR: ¹H NMR (400 MHz, CD₃OD) δ (ppm): 8.79 (s, 1H), 8.15 (d, J=15.8 Hz,2H), 7.75 (dd, J=6.5, 2.7 Hz, 1H), 7.44 (m, 1H), 7.24 (dd, J=10.2, 8.8Hz, 1H), 5.64 (s, 1H), 5.25 (s, 1H), 3.92 (m, 1H), 3.46-3.32 (m, 2H),2.20 (s, 3H), 1.20 (d, J=6.2 Hz, 3H). LCMS: 430.6 (M+1).

Example 21. Preparation of Compound Nos. 21, 21a and 21b Synthesis of3-[[2-(5-chloro-2-fluoro-phenyl)-5-isopropyl-4-pyridyl]amino]-N-(2-hydroxypropyl)-1H-pyrazole-4-carboxamide

To(S)-3-[[2-(5-chloro-2-fluoro-phenyl)-5-isopropenyl-4-pyridyl]amino]-N-(2-hydroxypropyl)-1H-pyrazole-4-carboxamide (10 mg, 0.023 mmol) in MeOH (1.5 mL)was added PtO₂ (2 mg) and conc. HCl (1 drop), and the reaction mixturewas hydrogenated using a hydrogen bladder for 90 min. The progress ofreaction was monitored by NMR. After completion the reaction, themixture was filtered through a celite bed. The filtrate was washed withMeOH and concentrated under reduced pressure to get crude product. Thecrude product was purified by preparative HPLC giving3-[[2-(5-chloro-2-fluoro-phenyl)-5-isopropyl-4-pyridyl]amino]-N-(2-hydroxypropyl)-1H-pyrazole-4-carboxamide(2.1 mg). The (R) enantiomer can be synthesized utilizing the(R)-enantiomeric starting material.

NMR: ¹H NMR (400 MHz, CD₃OD) δ (ppm): 8.75 (s, 1H), 8.30 (s, 1H), 8.16(s, 1H), 7.73 (dd, J=6.5, 2.7 Hz, 1H), 7.43 (m, 1H), 7.23 (dd, J=10.2,8.8 Hz, 1H), 3.95 (td, J=6.8, 4.8 Hz, 1H), 3.42 (dd, J=13.7, 4.6 Hz,2H), 3.31-3.15 (m, 2H), 1.44 (d, J=6.8 Hz, 6H), 1.21 (d, J=6.3 Hz, 4H).LCMS: 432.5 (M+1).

Example 22. Preparation of Compound No. 22 Synthesis of4-[[2-(5-chloro-2-fluoro-phenyl)-5-isopropyl-4-pyridyl]amino]-N-[2-hydroxy-1-(hydroxymethyl)ethyl]pyridine-3-carboxamide

Steps 1 to 8 are the same as in Comparative Example 1

Step 9: Synthesis of4-[[2-(5-chloro-2-fluoro-phenyl)-5-isopropyl-4-pyridyl]amino]-N-[2-hydroxy-1-(hydroxymethyl)ethyl]pyridine-3-carboxamide

To a solution of4-[[2-(5-chloro-2-fluoro-phenyl)-5-isopropyl-4-pyridyl]amino]pyridine-3-carboxylicacid (100 mg, 0.245 mmol) in DMF (4 mL) was added N,N-diisopropylethylamine (0.17 mL, 0.98 mmol) and PYBOP (254 mg, 0.829 mmol) and thereaction mixture was stirred at RT for 15 min under nitrogen atmosphere.Then, to this reaction mixture was added a solution of2-aminopropane-1,3-diol (33 mg, 0.367 mmol) in DMF (1 mL) and thereaction mixture was stirred at RT overnight. The progress of reactionwas monitored by TLC. After completion of reaction, the mixture wasdiluted with water and extracted with EtOAc (50 mL). The organic layerwas washed with water (2×10 mL) and brine solution (10 mL). The combinedorganic layer was dried over anhydrous sodium sulfate and evaporatedunder reduced pressure to obtain oily crude compound which was purifiedby reverse phase HPLC to afford4-[[2-(5-chloro-2-fluoro-phenyl)-5-isopropyl-4-pyridyl]amino]-N-[2-hydroxy-1-(hydroxymethyl)ethyl]pyridine-3-carboxamide(10 mg).

NMR: ¹H NMR (400 MHz, CD₃OD) δ (ppm): 8.80 (s, 1H), 8.58 (s, 1H), 8.32(d, J=6.0 Hz, 1H), 7.89 (dd, J=6.6, 2.8 Hz, 1H), 7.80 (d, J=1.8 Hz, 1H),7.50-7.34 (m, 2H), 7.25 (dd, J=10.7, 8.8 Hz, 1H), 4.24 (p, J=5.7 Hz,1H), 3.82-3.68 (m, 4H), 3.30-3.18 (m, 1H), 1.40 (d, J=6.9 Hz, 6H).

Example 23. Preparation of Compound Nos. 23, 23a and 23b Synthesis of4-[[2-amino-6-(5-chloro-2-fluoro-phenyl)-3-isopropenyl-4-pyridyl]amino]-N-[(2S)-2-hydroxypropyl]pyridine-3-carboxamide

Step 1: Synthesis of methyl 2-amino-4,6-dihydroxy-pyridine-3-carboxylate

A mixture of dimethyl 1,3-acetonedicarboxylate (50 g, 0.287 mol),cyanamide (36.17 g, 0.861 mol) and nickel(II) acetylacetonate (7.376 g,0.0287 mol) in 1,4-dioxane (300 mL) was heated to reflux for 16 h. Then,the reaction mixture was cooled to RT and stirred for 1 h. The reactionmixture was filtered and the resulting residue was filtered. The residuewas mixed with MeOH (100 mL) and stirred for 1 h and filtered to affordmethyl 2-amino-4,6-dihydroxy-pyridine-3-carboxylate (44 g) as a yellowsolid.

Step 2: Synthesis of methyl 2-amino-4,6-dichloro-pyridine-3-carboxylate

Phosphorous oxychloride (225 mL) was added to methyl2-amino-4,6-dihydroxy-pyridine-3-carboxylate (44 g, 0.239 mol) at 0° C.under nitrogen atmosphere. To this reaction mixture was addedN,N-diisopropylethyl amine (44 mL) at the same temperature and thereaction mixture was stirred at RT for 3 d. The progress of reactionmonitored by TLC and LCMS. After completion of reaction, the reactionmixture was concentrated under reduced pressure to obtain a stickycompound which was cooled to 0° C. and MeOH (40 mL) and water (200 mL)were added. The reaction mixture was stirred at RT for 1 h. Theresulting solid was filtered off and purified by column chromatographyon silica (100:200 mesh) using 10% EtOAc-hexane system as eluent toafford methyl 2-amino-4,6-dichloro-pyridine-3-carboxylate (20 g).

Step 3: Synthesis of 2-(2-amino-4,6-dichloro-3-pyridyl)propan-2-ol

To a solution of methyl 2-amino-4,6-dichloro-pyridine-3-carboxylate (300mg, 1.357 mmol) in dry THF (7 mL) was added a 3M solution ofmethylmagnesium bromide in diethyl ether (1.58 mL, 4.75 mmol) dropwiseunder nitrogen at −60° C. The reaction mixture was stirred at −60° C. to0° C. for 1 h. The progress of reaction was monitored by TLC & ¹H NMR.After completion of reaction, the mixture was quenched using aqueoussaturated solution of ammonium chloride and extracted with EtOAc. Theorganic layer was washed with water and brine, dried over anhydroussodium sulfate and concentrated under reduced pressure to obtain thecrude product. The crude product was purified by column chromatographyon silica (100:200 mesh) using 10% EtOAc-hexane system as eluent toafford 2-(2-amino-4,6-dichloro-3-pyridyl)propan-2-ol (263 mg).

Step 4: Synthesis of2-[2-amino-4-chloro-6-(5-chloro-2-fluoro-phenyl)-3-pyridyl]propan-2-ol

A suspension of 2-(2-amino-4,6-dichloro-3-pyridyl)propan-2-ol (3.5 g,0.0158 mole); (5-chloro-2-fluoro-phenyl) boronic acid (4.409 g, 0.0253mol) and cesium carbonate (10.32 g, 0.0316 mol) in 2:1 mixture ofDMF:H₂O (50 mL). This mixture was purged with nitrogen for 45 min. Then,to this reaction mixture was added Pd(PPh₃)₄ (1.829 g, 0.00158 mol) andpurging continued with nitrogen for further 10 min. The resultingreaction mixture was heated at 95° C. overnight. After completion ofreaction, the reaction mixture was diluted with water, extracted withEtOAc. The organic layer was washed with water and brine solution, driedover anhydrous sodium sulfate and concentrated under reduced pressure toobtain the crude product. The crude product was purified by columnchromatography on silica (100:200 mesh) using 8% EtOAc-hexane system aseluent to afford2-[2-amino-4-chloro-6-(5-chloro-2-fluoro-phenyl)-3-pyridyl]propan-2-ol(1.38 g) pure compound as a sticky yellow solid.

Step 5: Synthesis of4-chloro-6-(5-chloro-2-fluoro-phenyl)-3-isopropenyl-pyridin-2-amine

2-[2-amino-4-chloro-6-(5-chloro-2-fluoro-phenyl)-3-pyridyl]propan-2-ol(1.04 g, 0.0033 mol) in polyphosphoric acid (10 g) was heated at 120° C.for 2 h. The progress of reaction was monitored by TLC and LCMS. Aftercompletion of reaction, the mixture was cooled to 0° C., diluted withwater, basified with a saturated aqueous solution of sodium hydroxide(pH 10-12) and extracted with EtOAc. The organic layer was washed withwater and brine solution, dried over anhydrous sodium sulfate andconcentrated under reduced pressure to afford4-chloro-6-(5-chloro-2-fluoro-phenyl)-3-isopropenyl-pyridin-2-amine (850mg) as a pure compound.

Step 6: Synthesis of tert-butylN-[4-chloro-6-(5-chloro-2-fluoro-phenyl)-3-isopropenyl-2-pyridyl]carbamate

To a solution of4-chloro-6-(5-chloro-2-fluoro-phenyl)-3-isopropenyl-pyridin-2-amine(3.25 g, 0.019 mol) in DCM (30 mL) was added TEA (3 mL) followed by DMAP(0.267 g, 0.00218 mol) under nitrogen atmosphere and stirred at RT for15 min. To this reaction mixture was added (BOC)₂O (3.104 g, 0.01425mol) and stirred overnight at RT. The progress of reaction was monitoredby TLC and LCMS. After completion of reaction, the mixture was dilutedwith DCM and washed with water and brine solution. The organic layer wasdried over anhydrous sodium sulfate and concentrated under reducedpressure to obtain the crude which was purified by column chromatographyon silica gel (100:200 mesh) using 1% EtOAc-hexane system as eluent toafford tert-butylN-[4-chloro-6-(5-chloro-2-fluoro-phenyl)-3-isopropenyl-2-pyridyl]carbamate(3.2 g).

Step 7: Synthesis of methyl4-[[2-(tert-butoxycarbonylamino)-6-(5-chloro-2-fluoro-phenyl)-3-isopropenyl-4-pyridyl]amino]pyridine-3-carboxylate

A suspension of tert-butylN-[4-chloro-6-(5-chloro-2-fluoro-phenyl)-3-isopropenyl-2-pyridyl]carbamate(3.2 g, 0.0062 mol), methyl 4-aminopyridine-3-carboxylate (1.137 g,0.0074 mol) and potassium phosphate tribasic (2.64 g, 0.01247 mol) indioxane (40 mL) was purged with nitrogen for 45 min. To this reactionmixture was added Xantphos (0.721 g, 0.001247 mol) and Pd₂(dba)₃ (0.856g, 0.00093 mol) and purging continued with nitrogen for 10 min. Theresulting mixture was heated at 100° C. for 18 h. The progress ofreaction was monitored by TLC and LCMS. After completion of reaction,the mixture was filtered through a celite bed. The filtrate wasconcentrated under reduced pressure to obtain oily crude compound thatwas purified by column chromatography on silica gel (100:200 mesh) using25-30% EtOAc-hexane system as eluent to afford methyl4-[[2-(tert-butoxycarbonylamino)-6-(5-chloro-2-fluoro-phenyl)-3-isopropenyl-4-pyridyl]amino]pyridine-3-carboxylate(0.84 g) pure compound as a yellow solid.

Step 8: Synthesis of4-[[2-(tert-butoxycarbonylamino)-6-(5-chloro-2-fluoro-phenyl)-3-isopropenyl-4-pyridyl]amino]pyridine-3-carboxylicacid

To a suspension of methyl4-[[2-(tert-butoxycarbonylamino)-6-(5-chloro-2-fluoro-phenyl)-3-isopropenyl-4-pyridyl]amino]pyridine-3-carboxylate(500 mg, 0.814 mmol) in MeOH (10 mL) was added NaOH (52 mg, 1.3 mmol) inwater (1 mL) and heated at 80° C. for 2 h. The progress of reaction wasmonitored by TLC. After completion of reaction, the mixture wasconcentrated under reduced pressure to obtain a sticky compound. To thiswas added toluene (3×10 mL) to obtain a solid compound which wastriturated with diethyl ether (10 mL) to afford4-[[2-(tert-butoxycarbonylamino)-6-(5-chloro-2-fluoro-phenyl)-3-isopropenyl-4-pyridyl]amino]pyridine-3-carboxylic acid (500 mg) as a light yellow solid.

Step 9: Synthesis of afforded4-[[2-amino-6-(5-chloro-2-fluoro-phenyl)-3-isopropenyl-4-pyridyl]amino]pyridine-3-carboxylicacid

To a suspension of4-[[2-(tert-butoxycarbonylamino)-6-(5-chloro-2-fluoro-phenyl)-3-isopropenyl-4-pyridyl]amino]pyridine-3-carboxylicacid (100 mg, 0.16 mmol) in 10:1 mixture of DCM:DMF (10 mL) was addedTFA (1 mL) and stirred for 2 h. The progress of reaction was monitoredby TLC and LCMS. After completion of reaction, the mixture wasconcentrated under reduced pressure to obtain the crude product. Thecrude product was triturated with diethylether and dried in vacuo toafford4-[[2-amino-6-(5-chloro-2-fluoro-phenyl)-3-isopropenyl-4-pyridyl]amino]pyridine-3-carboxylicacid (80 mg).

Step 10: Synthesis of4-[[2-amino-6-(5-chloro-2-fluoro-phenyl)-3-isopropenyl-4-pyridyl]amino]-N-[(2S)-2-hydroxypropyl]pyridine-3-carboxamide

To a stirred solution of4-[[2-amino-6-(5-chloro-2-fluoro-phenyl)-3-isopropenyl-4-pyridyl]amino]pyridine-3-carboxylicacid (80 mg, 0.127 mmol) in DMF (4 mL) added N,N-diisopropylethyl amine(0.09 mL, 0.51 mmol) and HATU (78 mg, 0.204 mmol) and stirred for 15 minat RT under nitrogen atmosphere. To this reaction mixture was added(S)-1-aminopropan-2-ol (24 mg, 0.318 mmol) and the reaction mixture wasstirred at RT for 4 h. The progress of reaction was monitored by TLC andLCMS. After completion of reaction, the mixture was diluted with waterand extracted with EtOAc. The organic layer was washed with brine andwater, dried over anhydrous sodium sulfate and concentrated underreduced pressure to obtain the crude product. The crude product waspurified by reverse phase HPLC to afford4-[[2-amino-6-(5-chloro-2-fluoro-phenyl)-3-isopropenyl-4-pyridyl]amino]-N-[(2S)-2-hydroxypropyl]pyridine-3-carboxamide(6.5 mg) as a white solid. The (R) enantiomer can be synthesizedutilizing (R)-1-aminopropan-2-ol in this step.

NMR: ¹H NMR (400 MHz, CDCl₃) δ (ppm): 10.12 (s, 1H), 8.73 (s, 1H), 8.34(s, 1H), 7.97 (dd, J=6.7, 2.8 Hz, 1H), 7.36 (s, 1H), 7.33-7.22 (m, 2H),7.06 (dd, J=10.6, 8.7 Hz, 1H), 6.96 (s, 1H), 5.64 (d, J=2.2 Hz, 1H),5.22 (s, 1H), 4.69 (s, 2H), 4.06 (m, 1H), 3.67 (d, J=13.8 Hz, 1H),3.34-3.24 (m, 1H), 2.05 (s, 3H), 1.27 (t, J=6.2 Hz, 3H).

Example 24. Preparation of Compound Nos. 24, 24a and 24b Synthesis of4-[[2-(5-chloro-2-fluoro-phenyl)-5-isopropenyl-4-pyridyl]amino]-N-[(1S)-1-(hydroxymethyl)propyl]pyridine-3-carboxamide

To a solution of methyl4-[[2-(5-chloro-2-fluoro-phenyl)-5-isopropenyl-4-pyridyl]amino]pyridine-3-carboxylate(100 mg, 0.25 mmol) and (2S)-2-aminobutan-1-ol (45 mg, 0.5 mmol) intoluene (5 mL) was added a 1 M solution of trimethylaluminium) inheptane (1 mL, 1.005 mmol) and heated at 120° C. for 4 h. The progressof reaction was monitored by TLC and LCMS. After completion of reaction,the mixture was cooled to RT and diluted with water and EtOAc. Theorganic layer was washed with water and brine solution, dried overanhydrous sodium sulfate and concentrated under reduced pressure toobtain the crude product. The crude product was purified by CombiFlash®chromatography to afford a residue which was triturated with n-pentaneand dried under vacuum to afford4-[[2-(5-chloro-2-fluoro-phenyl)-5-isopropenyl-4-pyridyl]amino]-N-[(1S)-1-(hydroxymethyl)propyl]pyridine-3-carboxamide(43 mg). The (R) enantiomer can be synthesized utilizing(2R)-2-aminobutan-1-ol in this step.

NMR: ¹H NMR (400 MHz, DMSO-d6) (ppm): 10.42 (s, 1H), 8.81 (s, 1H), 8.46(d, J=9.3 Hz, 2H), 8.39 (d, J=5.8 Hz, 1H), 7.99 (dd, J=6.7, 2.8 Hz, 1H),7.84 (s, 1H), 7.60-7.49 (m, 1H), 7.41 (dd, J=11.9, 7.4 Hz, 2H), 5.48 (s,1H), 5.20 (s, 1H), 4.70 (t, J=5.8 Hz, 1H), 3.88 (td, J=8.6, 4.5 Hz, 1H),3.43 (m, 2H), 2.09 (s, 3H), 1.65 (m, 1H), 1.53-1.37 (m, 1H), 0.88 (t,J=7.5 Hz, 3H).

Example 25a. Preparation of Compound No. 25a Synthesis of4-[[2-(5-chloro-2-fluoro-phenyl)-5-vinyl-4-pyridyl]amino]-N-[(1R)-1-(hydroxymethyl)-2-methyl-propyl]pyridine-3-carboxamide

To a solution of methyl4-[[2-(5-chloro-2-fluoro-phenyl)-5-isopropenyl-4-pyridyl]amino]pyridine-3-carboxylate(100 mg, 0.25 mmol) and ((2R)-2-amino-3-methyl-butan-1-ol (52 mg, 0.502mmol) in toluene (5 mL) was added a 1 M solution of trimethylaluminiumin heptane (1 mL, 1.005 mmol) and heated at 120° C. for 4 h. Theprogress of reaction was monitored by TLC and LCMS. After completion ofreaction, the mixture was cooled to RT and diluted with water and EtOAc.The organic layer was washed with water and brine solution, dried overanhydrous sodium sulfate and concentrated under reduced pressure toobtain the crude product. The crude product was purified by reversephase HPLC to afford4-[[2-(5-chloro-2-fluoro-phenyl)-5-vinyl-4-pyridyl]amino]-N-[(1R)-1-(hydroxymethyl)-2-methyl-propyl]pyridine-3-carboxamide(13.8 mg).

NMR: ¹H NMR (400) MHz, CDCl₃) δ (ppm): 10.13 (s, 1H), 8.68 (s, 1H), 8.50(s, 1H), 8.39 (d, J=5.9 Hz, 1H), 8.02 (dd, J=6.8, 2.7 Hz, 1H), 7.84-7.78(m, 1H), 7.41-7.21 (m, 2H), 7.10 (dd, J=10.7, 8.7 Hz, 1H), 6.57 (d,J=8.8 Hz, 1H), 5.47 (s, 1H), 5.21 (s, 1H), 3.96 (m, 1H), 3.82 (d, J=4.3Hz, 2H), 2.15-1.97 (m, 4H), 1.04 (t, J=6.9 Hz, 6H).

Example 25b. Preparation of Compound No. 25b Synthesis of4-[[2-(5-chloro-2-fluoro-phenyl)-5-vinyl-4-pyridyl]amino]-N-[(1S)-1-(hydroxymethyl)-2-methyl-propyl]pyridine-3-carboxamide

To a solution of methyl4-[[2-(5-chloro-2-fluoro-phenyl)-5-isopropenyl-4-pyridyl]amino]pyridine-3-carboxylate(100 mg, 0.25 mmol) and ((2R)-2-amino-3-methyl-butan-1-ol (52 mg, 0.502mmol) in toluene (5 mL) was added a 1 M solution of trimethylaluminiumin heptane (1 mL, 1.005 mmol) and heated at 120° C. for 4 h. Theprogress of reaction was monitored by TLC and LCMS. After completion ofreaction, the mixture was cooled to RT and diluted with water and EtOAc.The organic layer was separated, washed with water and brine solution,dried over anhydrous sodium sulfate and concentrated under reducedpressure to obtain the crude product. The crude product was purified byreverse phase HPLC to afford4-[[2-(5-chloro-2-fluoro-phenyl)-5-vinyl-4-pyridyl]amino]-N-[(1S)-1-(hydroxymethyl)-2-methyl-propyl]pyridine-3-carboxamide(14.58 mg).

NMR: ¹H NMR (400 MHz, CDCl₃) δ (ppm): 10.13 (s, 1H), 8.68 (s, 1H), 8.50(s, 1H), 8.40 (d, J=5.9 Hz, 1H), 8.02 (dd, J=6.8, 2.7 Hz, 1H), 7.81 (d,J=1.7 Hz, 1H), 7.41-7.27 (m, 2H), 7.10 (dd, J=10.7, 8.7 Hz, 1H), 6.57(d, J=8.7 Hz, 1H), 5.47 (s, 1H), 5.21 (s, 1H), 3.97 (m, 1H), 3.82 (d,J=4.3 Hz, 2H), 2.15-1.97 (m, 4H), 1.04 (t, J=6.9 Hz 6H). Example 26.

Preparation of Compound No. 26 Synthesis of4-[[2-(5-chloro-2-fluoro-phenyl)-5-isopropenyl-4-pyridyl]amino]-N-(2-hydroxyethyl)pyridine-3-carboxamide

Steps 1 to 4 are the same as in Example 2

Step 5: Synthesis of4-[[2-(5-chloro-2-fluoro-phenyl)-5-isopropenyl-4-pyridyl]amino]-N-(2-hydroxyethyl)pyridine-3-carboxamide

To 2-aminoethanol (30 mg, 0.5 mmol) in toluene (4 mL) was added sodiummethoxide (13 mg, 0.25 mmol). The reaction mixture was stirred at RT for5 min. Then, to this reaction mixture was added methyl4-[[2-(5-chloro-2-fluoro-phenyl)-5-isopropenyl-4-pyridyl]amino]pyridine-3-carboxylate(100 mg, 0.25 mmol) and the reaction mixture was heated at 50° C. for 5h. The progress of reaction was monitored by LCMS. After completion ofthe reaction, the mixture was quenched with ice-cold water (15 mL) andthe product was extracted with EtOAc (2×250 mL). The combined organiclayer was washed with brine (50 mL), dried over sodium sulfate andconcentrated under reduced pressure to give a crude product. The crudeproduct was purified by preparative HPLC to afford4-[[2-(5-chloro-2-fluoro-phenyl)-5-isopropenyl-4-pyridyl]amino]-N-(2-hydroxyethyl)pyridine-3-carboxamide (29.28 mg) as the TFA salt.

NMR: ¹H NMR (400 MHz, CD₃OD) δ (ppm): 8.88 (s, 1H), 8.68 (s, 1H), 8.36(d, J=7.2 Hz, 1H), 8.02-7.91 (m, 2H), 7.56-7.44 (m, 2H), 7.29 (dd,J=10.7, 8.8 Hz, 1H), 5.53-5.45 (m, 1H), 5.29 (s, 1H), 3.75 (t, J=5.6 Hz,2H), 3.55 (t, J=5.5 Hz, 2H), 2.13 (s, 3H) LCMS: 425.4 (m−1).

Example 27. Preparation of Compound No. 27 Synthesis of4-[[2-(5-chloro-2-fluoro-phenyl)-5-isopropenyl-4-pyridyl]amino]-N-cyclopropyl-pyridine-3-carboxamide

Steps 1 to 4 are the same as in Example 2

Step 5: Synthesis of4-[[2-(5-chloro-2-fluoro-phenyl)-5-isopropenyl-4-pyridyl]amino]-N-cyclopropyl-pyridine-3-carboxamide

To methyl4-[[2-(5-chloro-2-fluoro-phenyl)-5-isopropenyl-4-pyridyl]amino]pyridine-3-carboxylate(100 mg, 0.25 mmol) and cyclopropanamine (28 mg, 0.5 mmol) in toluene (4mL) was added Me₃Al (1.0 mL, 1.00 mmol) and the reaction was heated at140° C. for 4 h. The progress of reaction was monitored by LCMS. Aftercompletion of reaction, the mixture was quenched with a saturatedaqueous solution of NaHCO₃ (20 mL) and the product was extracted withEtOAc (2×70 mL). The combined organic layer was washed with brine (30mL), dried over sodium sulfate and concentrated under reduced pressureto give a crude product. The crude compound was purified by preparativeHPLC to afford4-[[2-(5-chloro-2-fluoro-phenyl)-5-isopropenyl-4-pyridyl]amino]-N-cyclopropyl-pyridine-3-carboxamide(34.85 mg).

NMR: ¹H NMR (400 MHz, CD₃OD) δ (ppm): 8.79 (s, 1H), 8.68 (s, 1H), 8.34(d, J=7.2 Hz, 1H), 7.99 (dd, J=6.7, 2.8 Hz, 1H), 7.92 (s, 1H), 7.56-7.36(m, 2H), 7.29 (dd, J=10.8, 8.8 Hz, 1H), 5.54-5.48 (m, 1H), 5.29 (s, 1H),2.92 (tt, J=7.4, 3.9 Hz, 1H), 2.14 (s, 3H), 0.86 (m, 2H), 0.80-0.65 (m,2H). LCMS: 423.4 (M+1).

Example 28. Preparation of Compound Nos. 28, 28a and 28b Synthesis ofN-[(2S)-2-hydroxypropyl]-4-{[2-phenyl-5-(propan-2-yl)pyridin-4-yl]amino}pyridine-3-carboxamide

Step 1: Synthesis of 2-(4,6-dichloro-3-pyridyl)propan-2-ol

To a solution of methyl 4,6-dichloropyridine-3-carboxylate (5 g, 0.0243mol) in dry THF (60 mL) was added MeMgBr (3 M in THF, 28.3 mL) dropwiseat −60° C. under nitrogen atmosphere. The resultant reaction mixture wasallowed to warm to RT and stirred for 2 h. The progress of reaction wasmonitored over TLC. After completion of reaction, the reaction mixturewas cooled to 0° C. and quenched with saturated aqueous solution ofammonium chloride solution (200 mL) and extracted with EtOAc (2×300 mL).The combined organic layer was dried over anhydrous sodium sulfate andconcentrated under reduced pressure to afford2-(4,6-dichloro-3-pyridyl)propan-2-ol (4.91 g) as a yellow liquid.

Step 2: Synthesis of 2-(4-chloro-6-phenyl-3-pyridyl)propan-2-ol

To a solution of methyl 2-(4,6-dichloro-3-pyridyl)propan-2-ol (1.5 g,7.279 mmol), phenylboronic acid (1.150 g, 9.431 mmol) in DMF (24 mL) wasadded a solution of Na₂CO₃ (1.54 g, 14.529 mmol) in water (12 mL). Theresultant reaction mixture was purged with nitrogen for 30 min, followedby addition of tetrakis (673 mg, 0.582 mmol). The reaction mixture wasagain purged for 10 min and heated at 80° C. for 10 h. The progress ofreaction was monitored over TLC & LCMS. After completion of reaction,the reaction mixture was diluted with water (300 mL) and extracted withEtOAc (2×300) mL), dried over anhydrous sodium sulfate and concentratedunder reduced pressure to afford a crude product, which was purified bycolumn chromatography on silica gel (100-200 mesh) using110/EtOAc-hexane as eluent to obtain2-(4-chloro-6-phenyl-3-pyridyl)propan-2-ol (3.2 g) as an off whitesemi-solid.

Step 3: Synthesis of 4-chloro-5-isopropenyl-2-phenyl-pyridine

A mixture of 2-(4-chloro-6-phenyl-3-pyridyl)propan-2-ol (100 mg, 0.403mmol) and poly phosphoric acid (PPA, 1 g) was heated at 110° C. for 1 h.The progress of reaction was monitored by TLC. After the completion ofreaction, the reaction mixture was basified with aqueous KOH solutionand extracted with EtOAc (2×20 mL). The combined organic layer was driedover anhydrous sodium sulfate and concentrated under reduced pressure toafford 4-chloro-5-isopropenyl-2-phenyl-pyridine (75 mg) as an off whitesticky solid.

Step 4: Synthesis of 4-aminopyridine-3-carboxylic acid

A solution of 4-chloropyridine-3-carboxylic acid (15 g, 0.095 mol) inaqueous NH₃ (600 mL) was heated in a pressure vessel at 150° C.overnight. The progress of reaction was monitored by TLC. Aftercompletion of the reaction, the reaction mixture was concentrated underreduced pressure. To this concentrated reaction mixture was addedtoluene to (2×100 mL) to obtain 4-aminopyridine-3-carboxylic acid (17 g)as a white solid.

Step 5: Synthesis of methyl 4-aminopyridine-3-carboxylate

To a solution 4-aminopyridine-3-carboxylic acid (17 g, 0.123 mol) inmethanol (300 mL) was added sulfuric acid (45 mL) dropwise at 0° C. Theresultant reaction mixture was heated to reflux at 85° C. overnight. Theprogress of reaction was monitored by TLC. After the completion of thereaction, the reaction mixture was concentrated under reduced pressureto remove methanol, the residue was basified with saturated aqueoussolution of sodium carbonate (400 mL), and extracted with EtOAc (3×500mL). The combined organic layer was dried over anhydrous sodium sulfateand concentrated under reduced pressure to afford of methyl4-aminopyridine-3-carboxylate (10.3 g) as a white solid.

Step 6: Synthesis of methyl4-[(5-isopropenyl-2-phenyl-4-pyridyl)amino]pyridine-3-carboxylate

A mixture of 4-chloro-5-isopropenyl-2-phenyl-pyridine (1.2 g, 5.24mmol), methyl 4-aminopyridine-3-carboxylate (795 mg, 5.225 mmol) andCs2CO3 (3.40 g, 10.435 mmol) in dioxane (30 mL) was purged with nitrogenfor 30 min, followed by addition of Pd₂(dba)₃ (478 mg, 0.521 mmol) andxantphos (604 mg, 1.043 mmol) and again purged with nitrogen for 5 min.The reaction mixture was heated at 100° C. overnight. The progress ofreaction was monitored over LCMS. After completion of the reaction, thereaction mixture was diluted with water (100 mL) and extracted withEtOAc (2×150 mL). The combined organic layer was dried over anhydroussodium sulfate and concentrated under reduced pressure to afford a crudeproduct, which was purified by column chromatography on silica gel(100-200 mesh) using 20% EtOAc-hexane as eluent to obtain methyl4-[(5-isopropenyl-2-phenyl-4-pyridyl)amino]pyridine-3-carboxylate (500mg) as a yellow sticky semi-solid.

Step 7: Synthesis of methyl4-[(5-isopropyl-2-phenyl-4-pyridyl)amino]pyridine-3-carboxylate

To a solution of methyl4-[(5-isopropenyl-2-phenyl-4-pyridyl)amino]pyridine-3-carboxylate (1 g,2.895 mmol) in ethanol (30 mL) was added PtO₂ (225 mg). The resultantreaction mixture was allowed to stir at RT under hydrogen atmosphere(using a hydrogen bladder) for 7 h. The progress of reaction wasmonitored over ¹HNMR. After completion of reaction, the reaction mixturewas filtered through a celite bed. The organic layer was concentratedunder reduced pressure to afford methyl4-[(5-isopropyl-2-phenyl-4-pyridyl)amino]pyridine-3-carboxylate (890 mg)as a brown semi-solid.

Step 8: Synthesis ofN-(2-hydroxypropyl)-4-[(5-isopropyl-2-phenyl-4-pyridyl)amino]pyridine-3-carboxamide

A solution of (S)-1-aminopropan-2-ol (162 mg, 2.156 mmol) and (155 mg,1.381 mmol) in DCM (8 mL) was allowed to stir at RT for 30 min. To thisreaction mixture was added a solution of methyl4-[(5-isopropyl-2-phenyl-4-pyridyl)amino]pyridine-3-carboxylate (300 mg,0.863 mmol) in DCM (2 mL). The reaction mixture was heated at 50° C. for90 min. The progress of reaction was monitored over LCMS. Aftercompletion of the reaction, the reaction mixture was diluted with water(50 mL) and extracted with EtOAc (2×100 mL). The organic layer was driedover anhydrous sodium sulfate and concentrated under reduced pressure toafford a crude product, which was purified by reverse phase preparativeHPLC to obtainN-(2-hydroxypropyl)-4-[(5-isopropyl-2-phenyl-4-pyridyl)amino]pyridine-3-carboxamide(57 mg) as a white solid. The (R) enantiomer can be synthesizedutilizing (R)-1-aminopropan-2-ol in this step.

¹H NMR: (400 MHz, DMSO-d6) δ (ppm): 10.59 (s, 1H), 8.84 (m, 2H), 8.59(s, 1H), 8.34 (d, J=5.9 Hz, 1H), 8.13-7.87 (m, 2H), 7.81 (s, 1H), 7.45(m, 2H), 7.33-7.15 (m, 1H), 3.82 (h, J=6.2 Hz, 1H), 3.11 (m, 3H), 1.31(d, J=6.8 Hz, 6H), 1.09 (d, J=6.2 Hz, 3H).

Example 29. Preparation of Compound No. 29 Synthesis of2-(3-fluoropyridin-2-yl)-5-(propan-2-yl)-N-{1H-pyrrolo[2,3-b]pyridin-4-yl}pyridin-4-amine

Step-1: Synthesis of 2-(4, 6-dichloro-3-pyridyl)propan-2-ol

To a solution of methyl 4,6-dichloropyridine-3-carboxylate (5 g, 0.0243mol) in dry THF (60 mL) was added 3M solution of methyl magnesiumbromide in diethyl ether (28.3 mL, 0.0848 mol) dropwise under nitrogenatmosphere at −60° C. The resultant mixture was stirred at −60° C. to 0°C. for 2 h. The reaction was monitored by TLC & NMR. After completion ofreaction, the reaction mixture was quenched using aq. saturated ammoniumchloride solution and extracted with EtOAc. The organic layer washedwith water and brine solution, dried over anhydrous sodium sulfate andconcentrated under reduced pressure afforded2-(4,6-dichloro-3-pyridyl)propan-2-ol (4.96 g) as a yellow oil.

Step-2: Synthesis of 2,4-dichloro-5-isopropenyl-pyridine

To 2-(4,6-dichloro-3-pyridyl)propan-2-ol (200 mg, 0.97 mmol) was addedPPA (2 g) and heated at 120° C. for 90 min. The reaction was monitoredby TLC & LCMS. After completion of reaction, the reaction mixture wascooled to RT, basified with a saturated solution of NaOH solution up topH 12-14 and extracted with EtOAc (2×50 mL). The organic layer washedwith water (100 mL) and brine, dried over anhydrous sodium sulfate andconcentrated under reduced pressure to obtain the crude compound whichwas purified by column chromatography using silica 100:200 mesh andeluent 1% EtOAc in Hexane to afford 2,4-dichloro-5-isopropenyl-pyridine(150 mg).

Step-3: Synthesis of4-chloro-2-(3-fluoro-2-pyridyl)-5-isopropenyl-pyridine

2,4-Dichloro-5-isopropenyl-pyridine (900 mg, 4.787 mmol) and(3-fluoro-2-pyridyl) boronic acid (1.011 g, 7.180 mmol) were dissolvedin DMF (15 mL). To the stirred solution were added CsCO₃ (3.12 g, 9.574mmol). CuCl (236 mg, 2.393 mmol) and Pd(dppf) (26.87 mg, 0.1196 mmol)slowly at RT for 5 min. Then Pd(OAc)₂ (132.6 mg, 0.239 mmol) was addedand the resultant reaction mixture was kept at 100° C. overnight. Theprogress of the reaction was monitored by LCMS. On completion ofreaction, the reaction mixture was diluted with water (150 mL) and thereaction mixture was extracted with EtOAc (2×200 mL). The combinedorganic layer was washed with water (2×100 mL), brine solution (200 mL),dried over anhydrous sodium sulfate and concentrated under reducedpressure to obtain the crude compound, which was further purified bycolumn chromatography using silica gel 100:200 mesh, compound elutingwith 40% EtOAc:hexane to give pure4-chloro-2-(3-fluoro-2-pyridyl)-5-isopropenyl-pyridine (700 mg).

Step-4: Synthesis of4-chloro-1-[(4-methoxyphenyl)methyl]pyrrolo[2,3-b]pyridine

To a solution of 4-chloro-1H-pyrrolo[2,3-b]pyridine (7 g, 0.026 mmol) inDMF (5 mL) was added sodium hydride (55-60%) (1.56 g, 0.039 mmol)portionwise at 0° C. The reaction mixture was stirred at 0° C. to 10° C.for 30 min, followed by the slow addition of Para-methoxybenzyl chloride(5.319g, 0.0338 mmol) in DMF (5 mL). The reaction mixture was allowed tostir at 0° C. to 10° C. for 2 h. The reaction was monitored by TLC andLCMS. After completion of reaction, ice cold water (100 mL) was added tothe reaction mixture and product was extracted with EtOAc (2×200 mL).The combined organic layer was again washed with water (3×100 mL) andfinally with brine solution (2×75 mL). The organic layer was separated,dried over anhydrous sodium sulfate and concentrated under reducedpressure to afford a crude product which was purified by columnchromatography with silica gel 100:200 mesh in EtOAc:hexane productelutes at 5% to give4-chloro-1-[(4-methoxyphenyl)methyl]pyrrolo[2,3-b]pyridine as anoff-white solid (7 g).

Step 5: Synthesis ofN-[1-[(4-methoxyphenyl)methyl]pyrrolo[2,3-b]pyridin-4-yl]-2-methyl-propane-2-sulfinamide

To a solution of4-chloro-1-[(4-methoxyphenyl)methyl]pyrrolo[2,3-b]pyridine (5g, 0.0183mmol) was added cesium carbonate (2.66g, 0.0219 mmol) in dioxane (40 mL)then purged with nitrogen for 5 min. To this was added xantphos (0.634g, 0.0010 mmol) and palladium acetate (12 mg, 0.0005 mmol). The reactionmixture was heated in a reagent bottle at 100° C. overnight. Thereaction was monitored by TLC and LCMS. After completion of reaction,the reaction mixture was filtered through celite, the celite bed waswashed with EtOAc (2×100 mL). The filtrate obtained was concentratedunder reduced pressure. The crude product obtained was purified bycolumn chromatography on silica gel 100:200 mesh. The product elutes at20% EtOAc:Hexane to giveN-[1-[(4-methoxyphenyl)methyl]pyrrolo[2,3-b]pyridin-4-yl]-2-methyl-propane-2-sulfinamide(2 g).

Step-6: Synthesis of1-[(4-methoxyphenyl)methyl]pyrrolo[2,3-b]pyridin-4-amine

To a solution ofN-[1-[(4-methoxyphenyl)methyl]pyrrolo[2,3-b]pyridin-4-yl]-2-methyl-wasadded 4M HCl in dioxane (15 mL) dropwise at 0° C. under nitrogenatmosphere. The reaction mixture was kept at RT for 1 h. The reactionwas monitored by TLC and LCMS. After completion of reaction, thereaction mixture was neutralized by NaHCO₃ to pH 6-7. Then the productwas extracted with EtOAc (2×100 mL). The combined organic layer wasagain washed with water (100 mL) and finally with brine solution (2×75mL). The organic layer was separated, dried over anhydrous sodiumsulfate and concentrated under reduced pressure to afford crude1-[(4-methoxyphenyl)methyl]pyrrolo[2,3-b]pyridin-4-amine (2.5 g).

Step-7: Synthesis ofN-[2-(3-fluoro-2-pyridyl)-5-isopropenyl-4-pyridyl]-1-[(4-methoxyphenyl)methyl]pyrrolo[2,3-b]pyridin-4-amine

A suspension of 1-[(4-methoxyphenyl)methyl]pyrrolo[2,3-b]pyridin-4-amine (430 mg, 1.699 mmol),4-chloro-2-(3-fluoro-2-pyridyl)-5-isopropenyl-pyridine (424 mg, 1.699mmol) and cesium carbonate (1.104 g, 3.398 mmol) in dioxane (15 mL) waspurged for 20 min and xantphos (147.303 mg: 0.2548 moles), Pd₂(dba)₃(311.18 mg, 0.339 mmol) were added and the mixture purged for 5 min. Thereaction mixture was heated in a reagent bottle at 100° C. overnight.The reaction was monitored by TLC and LCMS. After completion of reactionmixture was filtered through celite, the celite bed was washed withEtOAc (2×100 mL). The filtrate obtained was concentrated under reducedpressure. The crude product was purified by column chromatography onsilica gel 100:200 mesh. The product elutes at 55% EtOAc:hexane to giveN-[2-(3-fluoro-2-pyridyl)-5-isopropenyl-4-pyridyl]-1-[(4-methoxyphenyl)methyl]pyrrolo[2,3-b]pyridin-4-amine (490 mg).

Step-8: Synthesis ofN-[2-(3-fluoro-2-pyridyl)-5-isopropyl-4-pyridyl]-1-[(4-methoxyphenyl)methyl]pyrrolo[2,3-b]pyridin-4-amine

To a stirred solution ofN-[2-(3-fluoro-2-pyridyl)-5-isopropenyl-4-pyridyl]-1-[(4-methoxyphenyl)methyl]pyrrolo[2,3-b]pyridin-4-amine(480 mg, 0.953 mmol) in ethanol (5 mL) and EtOAc (0.4 mL), PtO₂ (100 mg)was added at RT under H₂ atmosphere using a hydrogen bladder. Thereaction was kept on continuous stirring overnight. Completion ofreaction was monitored by LCMS and NMR. On completion of reaction, thereaction mixture was filtered through a celite bed. The filtrateobtained was concentrated under reduced pressure to obtainN-[2-(3-fluoro-2-pyridyl)-5-isopropyl-4-pyridyl]-1-[(4-methoxyphenyl)methyl]pyrrolo[2,3-b]pyridin-4-amine was obtained (450 mg).

Step-9: Synthesis ofN-[2-(3-fluoro-2-pyridyl)-5-isopropyl-4-pyridyl]-1H-pyrrolo[2,3-b]pyridin-4-amine

N-[2-(3-Fluoro-2-pyridyl)-5-isopropyl-4-pyridyl]-1-[(4-methoxyphenyl)methyl]pyrrolo[2,3-b]pyridin-4-amine (450 mg, 0.963 mmol) in TFA (8 mL) was addedtriflic acid (3 mL) and the reaction was heated at 60° C. for 1 h.Completion of reaction was monitored by TLC and LCMS. On completion ofreaction, the reaction mixture was concentrated under reduced pressureto obtain an oily compound which was neutralized by aq. saturated NaHCO₃and extracted with EtOAc (2×100 mL). The organic layer was again washedwith brine, dried over anhydrous sodium sulfate and concentrated underreduced pressure to afford a crude product which was purified by reversephase HPLC to obtainN-[2-(3-fluoro-2-pyridyl)-5-isopropyl-4-pyridyl]-1H-pyrrolo[2,3-b]pyridin-4-amine(95 mg) as an off-white solid. This was dissolved in ethanolic HCl (10mL) and concentrated under reduced pressure to giveN-[2-(3-fluoro-2-pyridyl)-5-isopropyl-4-pyridyl]-1H-pyrrolo[2,3-b]pyridin-4-aminehydrochloride salt (96 mg) as an off-white solid.

¹H NMR: (400 MHz, Methanol-d4) δ (ppm): 8.96 (s, 1H), 8.84 (s, 1H), 8.77(d, J=5.3 Hz, 1H), 8.29 (d, J=6.7 Hz, 1H), 8.20 (t, J=6.1 Hz, 1H), 7.96(s, 1H), 7.57 (d, J=3.5 Hz, 1H), 7.27 (d, J=6.7 Hz, 1H), 6.76 (d, J=3.7Hz, 1H), 3.56 (h, J=6.8 Hz, 1H), 1.46 (d, J=6.8 Hz, 6H). LCMS: 348(M+1).

Example 30. Preparation of Compound No. 30 Synthesis of2-(3-fluoropyridin-2-yl)-5-(propan-2-yl)-N-{7H-pyrrolo[2,3-d]pyrimidin-4-yl}pyridin-4-amine

Steps 1-8: Synthesis ofN-[2-(3-fluoro-2-pyridyl)-5-isopropyl-4-pyridyl]-7-[(4-methoxyphenyl)methyl]pyrrolo[2,3-d]pyrimidin-4-amine

See Example 29.

Step 9: Synthesis ofN-[2-(3-fluoro-2-pyridyl)-5-isopropyl-4-pyridyl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine

A solution ofN-[2-(3-fluoro-2-pyridyl)-5-isopropyl-4-pyridyl]-7-[(4-methoxyphenyl)methyl]pyrrolo[2,3-d]pyrimidin-4-amine (290 mg, 0.618 mmol) in TFA (5mL) and triflic acid (2.5 mL) was heated at 70° C. for 5 h. Progress ofthe reaction was monitored by TLC & LCMS. After completion of reaction,the reaction mixture was cooled to RT and concentrated under reducedpressure to obtain an oily compound which was neutralized using aq.saturated sodium bicarbonate and extracted with EtOAc (2×100 mL). Thecombined organic layer was washed with brine solution (50 mL) and driedover anhydrous sodium sulfate and concentrate under reduced pressure toobtain the crude compound, which was purified by reverse phase HPLC toobtainN-[2-(3-fluoro-2-pyridyl)-5-isopropyl-4-pyridyl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine(15 mg).

¹H NMR: (400 MHz; Methanol-d4) δ (ppm): 8.70 (s, 1H), 8.56 (d, J=3.1 Hz,1H), 8.51 (d, J=5.1 Hz, 1H), 8.25 (d, J=5.1 Hz, 2H), 7.99 (dd, J=6.8,5.1 Hz, 1H), 7.25 (d, J=3.6 Hz, 1H), 6.66 (d, J=3.6 Hz, 1H), 3.43 (p,J=6.9 Hz, 1H), 1.38 (d, J=6.9 Hz, 6H). LCMS: 349 (M+1).

Example 31. Preparation of Compound Nos. 31, 31a and 31b Synthesis of4-{[2-(5-chloro-2-fluorophenyl)-5-cyclopropylpyridin-4-yl]amino}-N-[(2S)-2-hydroxypropyl]pyridine-3-carboxamide

STEP-1: Synthesis of 2,4-dichloro-5-cyclopropyl-pyridine

5-Bromo-2,4-dichloro-pyridine (1.5 g, 6.60 mmol), cyclopropyl boronicacid (1.14 g, 13.2 mmol) and sodium carbonate (2.1 g, 19.82 mmol) weredissolved in 1,4-dioxane:Water (20:5 mL). Nitrogen gas was purged for 10min. Then Pd(dppf)Cl₂.DCM (270 mg, 0.330 mmol) was added and theresulting mixture was heated at 100° C. for 3 h. Product formation wasconfirmed by TLC and LCMS. Then the reaction mixture was diluted withwater (50 mL) and extracted with EtOAc (2×100 mL). The combined organiclayer was dried over anhydrous sodium sulfate and concentrated. Thecrude product was passed through the CombiFlash® chromatography toafford 700 mg of 2,4-dichloro-5-cyclopropyl-pyridine.

STEP-2: Synthesis of4-chloro-2-(5-chloro-2-fluoro-phenyl)-5-cyclopropyl-pyridine

2,4-Dichloro-5-cyclopropyl-pyridine (700 mg, 3.72 mmol),(5-chloro-2-fluoro-phenyl)boronic acid (1.3 g, 7.44 mmol) and sodiumbicarbonate (626 mg, 7.44 mmol) were dissolved in DMF:Water (10:5 mL)and nitrogen was purged for 10 min. Then Pd(PPh₃)₂.Cl₂ and heated at 90°C. for 12 h. Product formation was confirmed by TLC and LCMS. Then thereaction mixture was diluted with water (50 mL) and extracted with EtOAc(2×100 mL). The combined organic layer was washed with water (5×50 mL)and dried over anhydrous sodium sulfate, and concentrated. The crudeproduct was passed through CombiFlash® chromatography to afford 400 mgof 4-chloro-2-(5-chloro-2-fluoro-phenyl)-5-cyclopropyl-pyridine.

STEP-3: Synthesis of4-[[2-(5-chloro-2-fluoro-phenyl)-5-cyclopropyl-4-pyridyl]amino]pyridine-3-carboxylate

4-Chloro-2-(5-chloro-2-fluoro-phenyl)-5-cyclopropyl-pyridine (300 mg,1.06 mmol), methyl 4-aminopyridine-3-carboxylate (244 mg, 1.60 mmol) andpotassium phosphate tribasic (566 mg, 2.66 mmol) were dissolved in1,4-dioxane (5 mL). Nitrogen gas was purged for 10 min. Then Pd₂(dba)₃(49 mg, 0.053 mmol) and xantphos (31 mg, 0.053 mmol) were added and theresulting mixture was heated at 180° C. in a microwave reactor for 30min. Product formation was confirmed by TLC and LCMS. Then the reactionmixture was diluted with water (50 mL) and extracted with EtOAc (2×100mL). The combined organic layer was dried over anhydrous sodium sulfateand concentrated. The crude product was passed through the CombiFlash®chromatography to afford 200 mg of methyl4-[[2-(5-chloro-2-fluoro-phenyl)-5-cyclopropyl-4-pyridyl]amino]pyridine-3-carboxylate.

STEP-4: Synthesis of4-[[2-(5-chloro-2-fluoro-phenyl)-5-cyclopropyl-4-pyridyl]amino]-N-[(2S)-2-hydroxypropyl]pyridine-3-carboxamide

Methyl4-[[2-(5-chloro-2-fluoro-phenyl)-5-cyclopropyl-4-pyridyl]amino]pyridine-3-carboxylate(200 mg, 0.503 mmol) and (S)-1-aminopropan-2-ol (227 mg, 3.00 mmol) weredissolved in 2 mL of DMSO and heated at 120° C. for 4 h. Productformation was confirmed by LCMS. Then the reaction mixture was dilutedwith water (50 mL) and extracted with EtOAc (2×50 mL). The combinedorganic layer was washed with water (5×20 mL) and dried over anhydroussodium sulfate, and concentrated. The crude product was passed overreverse phase HPLC to afford 45 mg of4-[[2-(5-chloro-2-fluoro-phenyl)-5-cyclopropyl-4-pyridyl]amino]-N-[(2S)-2-hydroxypropyl]pyridine-3-carboxamide.The (R) enantiomer can be synthesized utilizing (R)-1-aminopropan-2-olin this step.

¹H NMR: (400 MHz, CDCl₃): δ (ppm): 10.58 (bs, 1H), 8.75 (s, 1H), 8.42(m, 2H), 7.99 (m, 1H), 7.78 (s, 1H), 7.42 (d, 1H), 7.30 (m, 1H), 7.08(t, 1H), 6.92 (bs, 1H), 4.08 (m, 1H), 3.70 (m 1H), 3.32 (m 1H), 1.88 (m,1H), 1.30 (d, 3H), 1.18 (m, 2H), 0.75 (m, 2H).

Example 32. Preparation of Compound No. 32 Synthesis of2-(5-chloro-2-fluorophenyl)-5-cyclopropyl-N-{1H-pyrrolo[2,3-b]pyridin-4-yl}pyridin-4-amine

4-Chloro-2-(5-chloro-2-fluoro-phenyl)-5-cyclopropyl-pyridine (200 mg,0.709 mmol), 1H-pyrrolo[2,3-b]pyridin-4-amine (189 mg, 1.41 mmol) andpotassium phosphate tribasic (376 mg, 1.77 mmol) were dissolved in1,4-dioxane (5 mL). Nitrogen gas was purged for 10 min. Then Pd₂(dba)₃(33 mg, 0.035 mmol) and xantphos (21 mg, 0.035 mmol) were added and theresulting mixture was heated at 180° C. in microwave reactor for 30 min.Product formation was confirmed by LCMS. Then the reaction mixture wasdiluted with water (50 mL) and extracted with EtOAc (2×50 mL). Thecombined organic layer was dried over anhydrous sodium sulfate andconcentrated. The crude product was passed through reverse phase HPLC toafford 50 mg ofN-[2-(5-chloro-2-fluoro-phenyl)-5-cyclopropyl-4-pyridyl]-1H-pyrrolo[2,3-b]pyridin-4-amine.

¹H NMR: (400 MHz, CDCl₃): δ (ppm): 10.58 (bs, 1H), 8.75 (s, 1H), 8.42(m, 2H), 7.99 (m, 1H), 7.78 (s, 1H), 7.42 (d, 1H), 7.30 (m, 1H), 7.08(t, 1H), 6.92 (bs, 1H), 4.08 (m, 1H), 3.70 (m, 1H), 3.32 (m, 1H), 1.88(m, 1H), 1.30 (d, 3H), 1.18 (m, 2H), 0.75 (m, 2H).

Example 33. Preparation of Compound No. 33 Synthesis of4-{[2-(5-chloro-2-fluorophenyl)-5-(pyrrolidin-1-yl)pyridin-4-yl]amino}-N-(1,3-dihydroxypropan-2-yl)pyridine-3-carboxamide

Step-1: Synthesis of 4,6-dichloropyridine-3-carboxylic acid

To a stirred solution of methyl 4,6-dichloropyridine-3-carboxylate (15g, 0.0728 mol) in THF (100 mL) was added a solution of lithium hydroxidemonohydrate (8.737 g, 0.364 mol) in water (50 mL). The resultantreaction mixture was stirred at RT for 1.5 h. The reaction was monitoredby TLC. After completion of reaction, the pH of the aqueous layer wasadjusted to 2 by the addition of 2 N HCl (aq.) and product was extractedwith EtOAc (2×500 mL). The organic layer was separated, dried overanhydrous sodium sulfate and concentrated under reduced pressure toafford 4,6-dichloropyridine-3-carboxylic acid (13.5 g) as a white solid.

Step-2: Synthesis of tert-butyl N-(4,6-dichloro-3-pyridyl)carbamate

To a solution of 4,6-dichloropyridine-3-carboxylic acid (8.4 g, 43.75mmol) in dry DMF (30 mL) was added triethylamine (6.5 mL, 48.12 mmol) at0° C. followed by diphenylphosphoryl azide (10.37 mL, 48.12 mmol). Theresultant reaction mixture was stirred at RT for 1 h and poured onto amixture of ice-water-EtOAc. The product was extracted with EtOAc (2×200mL). The combined extracts were washed with water (2×100 mL), asaturated solution of sodium bicarbonate (50 mL) and finally with brinesolution (50 mL). The organic layer was separated, dried over anhydroussodium sulfate and concentrated under reduced pressure to afford a lightyellow solid which was dissolved in 80 mL of dry toluene and heated toreflux for 2 h. Then the reaction mixture was cooled to RT and t-butanol(25.1 mL, 262.5 mmol) was added. The resultant reaction mixture washeated at 90° C. for 4 h. The reaction was monitored by TLC. Aftercompletion, the reaction mixture was concentrated under reducedpressure, water was added to the residue and the product was extractedwith EtOAc (2×250 mL). Removal of EtOAc under reduced pressure affordedan oily residue that was purified by column chromatography on silica gel(100-200 mesh) using 1% EtOAc-hexane system as eluent to affordtert-butyl N-(4,6-dichloro-3-pyridyl)carbamate (6.9 g) as a light yellowliquid.

Step-3: Synthesis of 4,6-dichloropyridin-3-amine

To a stirred solution of tert-butyl N-(4, 6-dichloro-3-pyridyl)carbamate(6.9 g, 0.0262 mol) in DCM (20 mL) was added trifluoroacetic acid (8 mL)dropwise at 0° C. The reaction mixture was slowly warmed to RT andstirred for 90 min. The reaction was monitored by TLC. After completionof reaction, reaction mixture was concentrated under reduced pressure.To the residue was added saturated solution of sodium bicarbonate (30mL) and product was extracted with EtOAc (2×200 mL). The organic layerwas again washed with water (30 mL) and brine solution (30 mL). Theorganic layer was separated, dried over anhydrous sodium sulfate.Removal of EtOAc under reduced pressure afforded product which was againwashed with n-pentane and dried to afford 4,6-dichloropyridin-3-amine(3.8 g) as a light brown solid.

Step-4: Synthesis of 2,4-dichloro-5-pyrrolidin-1-yl-pyridine

To a stirred solution of 4,6-dichloropyridin-3-amine (3.9 g, 0.0239 mol)in dry DMF (35 mL) was added sodium hydride (1.914 g, 0.0478 mol, 60%suspension in mineral oil) under nitrogen atmosphere at 0° C. Thereaction mixture was stirred at this temperature for 30 min. Then1,4-dibromobutane (4.134 g, 0.0191 mol) was added dropwise. The reactionmixture was stirred at RT overnight. The reaction was monitored by TLCand LCMS. After completion of reaction, the reaction was quenched byaddition of ice-water (50 mL) and the product was extracted with EtOAc(2×150 mL). The organic layer was again washed with water (2×50 mL) andbrine solution (50 mL). The organic layer was separated, dried overanhydrous sodium sulfate and concentrated under reduced pressure toafforded an oily residue that was purified by column chromatography onsilica gel (100-200 mesh) using 0.5-1% EtOAc-hexane to afford2,4-dichloro-5-pyrrolidin-1-yl-pyridine (3.711 g) as an off-white solid.

Step-5: Synthesis of4-chloro-2-(5-chloro-2-fluoro-phenyl)-5-pyrrolidin-1-yl-pyridine

To a stirred solution of 2,4-dichloro-5-pyrrolidin-1-yl-pyridine (3.5 g,0.0161 mol), (5-chloro-2-fluoro-phenyl)boronic acid (3.36 g, 0.01963mol) in DMF (15 mL) was added a suspension of sodium bicarbonate (2.7 g,0.0322 mol) in water (15 mL) was purged nitrogen for 30 min. Thenbis(triphenylphosphine)palladium(II) dichloride (566 mg, 0.000806 mmol)was added to the reaction mixture and nitrogen gas was purged through itfor another 5 min. The reaction mixture was then heated at 80° C.overnight. The reaction was monitored by TLC and LCMS. After completionof reaction, the reaction mixture was cooled to RT and water (50 mL) wasadded to the reaction mixture and product was extracted with EtOAc(2×100 mL). The combined organic layer was washed with water (3×50 mL)and finally with brine solution (50 mL). The organic layer wasseparated, dried over anhydrous sodium sulfate and concentrated underreduced pressure to obtain the crude compound which was purified bycombi flash chromatography using 5% EtOAc in hexane elute to afford4-chloro-2-(5-chloro-2-fluoro-phenyl)-5-pyrrolidin-1-yl-pyridine (1.615g) as an off-white solid and also recover unreacted starting material(2,4-dichloro-5-pyrrolidin-1-yl-pyridine, 1.8 g).

Step-6: Synthesis of methyl4-[[2-(5-chloro-2-fluoro-phenyl)-5-pyrrolidin-1-yl-4-pyridyl]amino]pyridine-3-carboxylate

A stirred solution of4-chloro-2-(5-chloro-2-fluoro-phenyl)-5-pyrrolidin-1-yl-pyridine (1.2 g,3.85 mmol), methyl 4-aminopyridine-3-carboxylate (645 mg, 4.24 mmol) andpotassium phosphate (tribasic) (1.635 g, 7.712 mmol) in 1,4-dioxane (20mL) was purged with nitrogen for 30 min. Thentris(dibenzylidineacetone)dipalladium(0) (353 mg, 0.385 mmol) andxantphos (335 mg, 0.578 mmol) were added to the reaction mixture.Nitrogen gas was purged through it for another 5 min. The resultingreaction mixture was then heated at 100° C. overnight. The reaction wasmonitored by TLC and LCMS. After completion of reaction, reactionmixture was filtered through a celite bed. The celite bed was washedwith EtOAc (2×100 mL). The filtrate was concentrated under reducedpressure to afford a crude product which was purified by combi-flashchromatography using 25% EtOAc-hexane system as eluent to afford methyl4-[[2-(5-chloro-2-fluoro-phenyl)-5-pyrrolidin-1-yl-4-pyridyl]amino]pyridine-3-carboxylate(1.056 g) as a light yellow solid.

Step-7: Synthesis of obtain4-[[2-(5-chloro-2-fluoro-phenyl)-5-pyrrolidin-1-yl-4-pyridyl]amino]-N-[2-hydroxy-1-(hydroxymethyl)ethyl]pyridine-3-carboxamide

To a stirred suspension of methyl4-[[2-(5-chloro-2-fluoro-phenyl)-5-pyrrolidin-1-yl-4-pyridyl]amino]pyridine-3-carboxylate(120 mg, 0.281 mmol) and 2-aminopropane-1,3-diol (128 mg, 1.405 mmol) inDMF (3 mL) The resulting reaction mixture was heated at 90° C. for 5 h.The reaction was monitored by TLC and LCMS. After completion ofreaction, reaction mixture was cooled to RT and diluted with water (10mL) and extracted with EtOAc (2×50 mL), and the organic layer washedwith water (15 mL). The organic layer was dried over anhydrous sodiumsulfate and concentrated under reduced pressure to obtain the crudeproduct which was purified by reverse phase HPLC to afford4-[[2-(5-chloro-2-fluoro-phenyl)-5-pyrrolidin-1-yl-4-pyridyl]amino]-N-[2-hydroxy-1-(hydroxymethyl)ethyl]pyridine-3-carboxamide (75 mg) as an off-white solid, whichwas dissolved in ethanolic HCl (10 mL) and concentrated under reducedpressure to obtain4-[[2-(5-chloro-2-fluoro-phenyl)-5-pyrrolidin-1-yl-4-pyridyl]amino]-N-[2-hydroxy-1-(hydroxymethyl)ethyl]pyridine-3-carboxamide (76 mg) as the HCl salt.

¹H NMR: (400 MHz, Methanol-d4) δ (ppm): 8.90 (s, 1H), 8.33 (d, J=8.3 Hz,2H), 7.88 (d, J=11.0 Hz, 2H), 7.51 (m, 1H), 7.30 (t, J=9.7 Hz, 1H), 7.19(d, J=7.1 Hz, 1H), 4.26 (d, J=6.1 Hz, 1H), 3.76 (qd, J=11.2, 5.7 Hz,4H), 3.47 (m, 4H), 1.99 (m, 4H). LCMS: 486 (M+1).

Example 34. Preparation of Compound No. 34 Synthesis of2-(5-chloro-2-fluorophenyl)-5-(prop-1-en-2-yl)-N-[3-(pyrrolidine-1-carbonyl)pyridin-4-yl]pyridin-4-amine

To a solution of methyl4-[[2-(5-chloro-2-fluoro-phenyl)-5-isopropenyl-4-pyridyl]amino]pyridine-3-carboxylate(700 mg, 1.763 m mol) and added pyrrolidine (1.25 g, 17.63 mmol) andheated at 100° C. for 1 h in a microwave reactor. The progress of thereaction was monitored by TLC and LCMS. After completion of reaction,the mixture was diluted with water (20 mL) extracted with EtOAc (2×100mL) and washed with water (5×100 mL). The combined organic layer wasdried with anhydrous sodium sulfate and concentrated under reducedpressure to afford a crude product, which was purified by reverse phasepurification to afford 200 mg2-(5-chloro-2-fluorophenyl)-5-(prop-1-en-2-yl)-N-[3-(pyrrolidine-1-carbonyl)pyridin-4-yl]pyridin-4-amine.

¹HNMR: (Free Base, DMSO-d6): δ (ppm): 9.15 (bs, 1H) 8.58 (s, 1H), 8.42(s, 1H), 8.38 (d, 1H), 7.98 (m, 1H), 7.75 (s, 1H), 7.58 (m, 1H), 7.41(m, 2H), 5.42 (s, 1H) 5.18 (s, 1H), 3.52 (m, 2H), 3.42 (m, 2H), 2.15 (s,3H), 1.88 (m, 2H), 1.78 (m, 2H).

Example 35. Preparation of Compound No. 35 Synthesis of2-(5-chloro-2-fluorophenyl)-5-(propan-2-yl)-N-{7H-pyrrolo[2,3-d]pyrimidin-4-yl}pyridin-4-amine

Step-1: Synthesis ofN-[2-(5-chloro-2-fluoro-phenyl)-5-isopropenyl-4-pyridyl]-7-[(4-methoxyphenyl)methyl]pyrrolo[2,3-d]pyrimidin-4-amine

4-Chloro-2-(5-chloro-2-fluoro-phenyl)-5-isopropenyl-pyridine (1.0 g, 3.5mmol), 7-[(4-methoxyphenyl)methyl]pyrrolo[2,3-d]pyrimidin-4-amine(1.35g, 5.3 mmol) potassium phosphate (2.25g, 10.52 mmol) was dissolvedin 1,4-dioxane (20 ml)nitrogen gas was purged for 20 min. To it wasadded tris(dibenzylideneacetone)dipalladium(0) (324 mg, 0.35 mmol) andxantphos (418 mg, 0.72 mmol) and again degassed with nitrogen for 20 minand the reaction mass was heated to reflux overnight. The reaction wasmonitored by TLC and LCMS. The reaction mass was filtered through asmall bed of celite and concentrated under reduced pressure to get thecrude product that was purified by chromatography (eluent: 20-40% EtOAcin hexane) to obtain the pureN-[2-(5-chloro-2-fluoro-phenyl)-5-isopropenyl-4-pyridyl]-7-[(4-methoxyphenyl)methyl]pyrrolo[2,3-d]pyrimidin-4-amine(530 mg).

Step-2: Synthesis ofN-[2-(5-chloro-2-fluoro-phenyl)-5-isopropyl-4-pyridyl]-7-[(4-methoxyphenyl)methyl]pyrrolo[2,3-d]pyrimidin-4-amine

N-[2-(5-Chloro-2-fluoro-phenyl)-5-isopropenyl-4-pyridyl]-7-[(4-methoxyphenyl)methyl]pyrrolo[2,3-d]pyrimidin-4-amine (502 mg, 1 mmol) was dissolved in asolution of ethanol and EtOAc (1:1) (10 mL), and to it was addedplatinum oxide (45 mg, 0.20 mmol) and the reaction mass was purged byHydrogen, with Hydrogen gas bladder for 3 h and kept under a hydrogenatmosphere overnight. The reaction was monitored by NMR. The reactionmass was filtered through a small bed of celite and concentrated underreduced pressure to obtain the product that was purified bychromatography (eluent: 50% EtOAc in hexane) to obtain the pureN-[2-(5-chloro-2-fluoro-phenyl)-5-isopropyl-4-pyridyl]-7-[(4-methoxyphenyl)methyl]pyrrolo[2,3-d]pyrimidin-4-amine(340 mg).

Step-3: Synthesis of2-(5-chloro-2-fluorophenyl)-5-(propan-2-yl)-N-{7H-pyrrolo[2,3-d]pyrimidin-4-yl}pyridin-4-amine

N-[2-(5-Chloro-2-fluoro-phenyl)-5-isopropyl-4-pyridyl]-7-[(4-methoxyphenyl)methyl]pyrrolo[2,3-d]pyrimidin-4-amine (250 mg, 0.5 mmol) was dissolved intrifluoroacetic acid (0.8 mL), and to it was addedtrifluoromethanesulfonic acid (0.2 mL) and the reaction mass was heatedin a microwave at 120° C. for 50 min. The reaction was monitored byLCMS. The reaction mass was basified with ice cold saturated sodiumhydrogen carbonate (20 mL) and extracted with DCM (2×20 mL). Thecombined organics were dried over sodium sulfate and concentrated underreduced pressure to obtain the product that was purified bychromatography (mobile phase (0-5% methanol in DCM) to obtain theproduct (120 mg). This product was again purified with reverse phaseHPLC to obtain the pure product2-(5-chloro-2-fluorophenyl)-5-(propan-2-yl)-N-{7H-pyrrolo[2,3-d]pyrimidin-4-yl}pyridin-4-amineas free base (15 mg). ¹HNMR: (400 MHz: DMSO-d6) δ (ppm): 11.8 (bs 1H),9.02 (s, 1H), 8.82 (s, 1H), 8.2 (s, 1H), 8.04 (s, 1H), 8.0 (d, 1H), 7.44(m, 1H), 7.40 (m, 1H), 7.22 (s, 1H), 6.6 (s, 1H), 3.4 (m, 1H), 1.2 (d,6H).

Example 36. Preparation of Compound No. 36 Synthesis of2-(5-chloro-2-fluorophenyl)-5-(propan-2-yl)-N-{1H-pyrazolo[3,4-d]pyrimidin-4-yl}pyridin-4-amine

Step-1: Synthesis ofN-[2-(5-chloro-2-fluoro-phenyl)-5-isopropenyl-4-pyridyl]-1-[(4-methoxyphenyl)methyl]pyrazolo[3,4-d]pyrimidin-4-amine

4-Chloro-2-(5-chloro-2-fluoro-phenyl)-5-isopropenyl-pyridine (2.0 g,7.09 mmol), 1-[(4-methoxyphenyl)methyl]pyrazolo[3,4-d]pyrimidin-4-amine(2.7 g, 10.6 mmol) and potassium phosphate (4.5 g, 21.2 mmol) weredissolved in 1,4-dioxane (40 mL), and the mixture purged with nitrogengas for 20 min. To this was added tris(dibenzylideneacetone)dipalladium(0) (324 mg, 0.35 mmol) and xantphos (418 mg, 0.72mmol) and again degassed with nitrogen for 20 min and the reaction masswas heated to reflux overnight. The reaction was monitored by TLC andLCMS. The reaction mass was filtered through a small bed of celite andconcentrated under reduced pressure to get the crude product that waspurified by chromatography (eluent: 20-40% EtOAc in hexane) to obtainthe pureN-[2-(5-chloro-2-fluoro-phenyl)-5-isopropenyl-4-pyridyl]-1-[(4-methoxyphenyl)methyl]pyrazolo[3,4-d]pyrimidin-4-amine(1.1 g).

Step-2: Synthesis ofN-[2-(5-chloro-2-fluoro-phenyl)-5-isopropyl-4-pyridyl]-1-[(4-methoxyphenyl)methyl]pyrazolo[3,4-d]pyrimidin-4-amine

N-[2-(5-Chloro-2-fluoro-phenyl)-5-isopropenyl-4-pyridyl]-1-[(4-methoxyphenyl)methyl]pyrazolo[3,4-d]pyrimidin-4-amine (1.0 g, 2.0 mmol) was dissolved in asolution of ethanol and EtOAc (1:1) (20 mL), and to it was addedplatinum oxide (90 mg, 0.39 mmol) and the reaction mass was purged withhydrogen gas, by bladder, for 3 h and kept under a hydrogen atmosphereovernight. The reaction was monitored by NMR. The reaction mass wasfiltered through a small bed of celite and concentrated under reducedpressure to obtain the product which was purified by chromatography(eluent: 50% EtOAc in hexane) to obtain the pure form ofN-[2-(5-chloro-2-fluoro-phenyl)-5-isopropyl-4-pyridyl]-1-[(4-methoxyphenyl)methyl]pyrazolo[3,4-d]pyrimidin-4-amine(650 mg).

Step-3: Synthesis of2-(5-chloro-2-fluorophenyl)-5-(propan-2-yl)-N-{1H-pyrazolo[3,4-d]pyrimidin-4-yl}pyridin-4-amine

N-[2-(5-Chloro-2-fluoro-phenyl)-5-isopropyl-4-pyridyl]-1-[(4-methoxyphenyl)methyl]pyrazolo[3,4-d]pyrimidin-4-amine (503 mg, 1.0 mmol) was dissolved intrifluoroacetic acid (0.8 mL), and to it was addedtrifluoromethanesulfonic acid (0.2 mL) and the reaction mass was heatedin a microwave at 120° C. for 50 min. The reaction was monitored byLCMS. The reaction mass was basified with ice cold saturated sodiumhydrogen carbonate (20 mL) and extracted with DCM (2×20 mL). Thecombined organics were dried over sodium sulfate and concentrated underreduced pressure to obtain the product that was purified bychromatography (mobile phase (0-5% methanol in DCM) to obtain theproduct (270 mg). that was again purified with reverse phase HPLC toobtain the pure product2-(5-chloro-2-fluorophenyl)-5-(propan-2-yl)-N-{1H-pyrazolo[3,4-d]pyrimidin-4-yl}pyridin-4-amineas formate salt (52 mg).

¹HNMR: (400 MHz: DMSO-d6) δ (ppm): 13.8-13.6 (bs, 1H) 10.0-9.8 (bs, 1H)8.8 (s, 1H), 8.2 (s, 1H), 8.14-8.0 (bs, 1H), 8.0 (d, 1H), 7.98 (s, 1H),7.6 (m, 1H), 7.4 (m, 1H), 3.2 (m, 1H), 1.2 (d, 6H).

Example 37. Preparation of Compound Nos. 37, 37a and 37b Synthesis of4-{[2-(2-fluorophenyl)-5-(prop-1-en-2-yl)pyridin-4-yl]amino}-N-[(2S)-2-hydroxypropyl]pyridine-3-carboxamide

Step-1: Synthesis of4-amino-N-[(2S)-2-hydroxypropyl]pyridine-3-carboxamide

(S)-1-Amino-2-propanol (2.0 g, 13.1 mmol) was added tomethyl-4-aminonicotinate (3.0 g, 39.9 mmol) in a microwave tube and theresulting mixture was heated in a microwave reactor at 120° C. for 1.5h. The product formation was confirmed by TLC and LCMS. The crudeproduct was purified by chromatography to afford 1.03 g of the product4-amino-N-[(2S)-2-hydroxpropyl]pyridine-3-carboxamide as white crystals.

Step-2: Synthesis of 4-chloro-2-(2-fluorophenyl)-5-isopropenyl-pyridine

A 100 mL screw cap bottle was charged with2,4-dichloro-5-isopropenyl-pyridine (2.0 g, 10.6 mmol),2-fluorophenylboronic acid (1.1 g, 8.0 mmol) and sodium carbonate (3.4g, 31.8 mmol) DME (20 ml) and water (5 mL) and degassed with nitrogenfor 15 min. To it was added Pd(PPh₃)₂.Cl₂ (364 mg, 0.52 mmol) anddegassed with nitrogen for another 10 min. The resulting mixture washeated at 100° C. for 3 h. The reaction was monitored by TLC and LCMS.Then the reaction mixture was passed through a celite bed, diluted withwater (25 mL) and EtOAc (25 mL). The layers were separated, and theaqueous layer was again extracted with EtOAc (50 mL). The combinedorganics were dried over anhydrous sodium sulfate and concentrated underreduced pressure to obtain the product, which was purified bychromatography (eluent: hexane) to afford 1.24 g of product4-chloro-2-(2-fluorophenyl)-5-isopropenyl-pyridine as white crystals.

Step-3: Synthesis of4-[[2-(2-fluorophenyl)-5-isopropenyl-4-pyridyl]amino]-N-[(2S)-2-hydroxypropyl]pyridine-3-carboxamide

A 25 mL screw cap bottle was charged with4-chloro-2-(2-fluorophenyl)-5-isopropenyl-pyridine (500 mg, 2.0 mmol),4-amino-N-[(2S)-2-hydroxypropyl]pyridine-3-carboxamide (433 mg, 2.2mmol), K₃PO₄ (849 mg, 4.0 mmol) and 1,4-dioxane (10 mL) and degassedwith nitrogen for 20 min. Then Xantphos (174 mg, 0.3 mmol) and Pd₂(dba)₃(183 mg, 0.2 mmol) were added and again degassed with nitrogen for afurther 15 min. The resulting mixture was heated at 100° C. overnight.The product formation was confirmed by LCMS. Then the reaction mixturewas passed through a celite bed and concentrated under reduced pressureto obtain the product, which was purified with reverse phase HPLC toafford 85 mg of product4-[[2-(2-fluorophenyl)-5-isopropenyl-4-pyridyl]amino]-N-[(2S)-2-hydroxypropyl]pyridine-3-carboxamideas a white solid. The (R) enantiomer can be synthesized utilizing(R)-1-aminopropan-2-ol in Step-1.

¹HNMR: (400 MHz, DMSO): δ (ppm): 10.43 (bs, 1H), 8.83-8.81 (m, 2H), 8.47(m, 1H), 7.99 (m, 1H), 7.78 (s, 1H), 7.42 (d, 1H), 7.30 (m, 1H), 7.08(t, 1H), 6.92 (bs, 1H), 4.08 (m, 1H), 3.70 (m, 1H), 3.32 (m, 1H), 1.88(m, 1H), 1.30 (d, 3H), 1.18 (m, 2H), 0.75 (m, 2H).

Example 38. Preparation of Compound Nos. 38, 38a and 38b Synthesis of4-{[2-(4-fluorophenyl)-5-(prop-1-en-2-yl)pyridin-4-yl]amino}-N-[(2S)-2-hydroxypropyl]pyridine-3-carboxamide

Step-1: Synthesis of4-amino-N-[(2S)-2-hydroxypropyl]pyridine-3-carboxamide

See Example 37.

Step-2: Synthesis of 4-chloro-2-(4-fluorophenyl)-5-isopropenyl-pyridine

A 100 mL screw cap bottle was charged with2,4-dichloro-5-isopropenyl-pyridine (2.0 g, 10.6 mmol),2-fluorophenylboronic acid (1.1 g, 8.0 mmol) and sodium carbonate (3.4g, 31.8 mmol) in a mixture of DME (20 mL) and water (5 mL) and degassedwith nitrogen for 15 min. Then Pd(PPh₃)₂.Cl₂ (364 mg, 0.52 mmol) wasadded and again degassed with nitrogen for a another 10 min. Theresulting mixture was heated at 100) ° C. for 3 h. The reaction wasmonitored by LCMS formation TLC and LCMS. Then the reaction mixture waspassed through a celite bed, diluted with water (25 mL) and extractedwith EtOAc (2×50 mL). The combined organic layer was dried overanhydrous sodium sulfate and concentrated under reduced pressure. Thecrude product was passed through the CombiFlash® chromatography toafford 1.41 g of product4-chloro-2-(4-fluorophenyl)-5-isopropenyl-pyridine as white crystals.

Step-3: Synthesis of4-{[2-(4-fluorophenyl)-5-(prop-1-en-2-yl)pyridin-4-yl]amino}-N-[(2S)-2-hydroxypropyl]pyridine-3-carboxamide

A 25 mL screw cap bottle was charged with4-chloro-2-(4-fluorophenyl)-5-isopropenyl-pyridine (500 mg, 2.0 mmol)and 4-amino-N-[(2S)-2-hydroxypropyl]pyridine-3-carboxamide (433 mg, 2.2mmol) and K₃PO₄ (849 mg, 4.0 mmol) and 1,4-dioxane (10 mL) and degassedwith nitrogen for 30 min. Then Xantphos (174 mg, 0.3 mmol) and Pd₂(dba)₃(183 mg, 0.2 mmol) were added and nitrogen was purged for further 15min. The resulting mixture was heated at 100° C. overnight. The reactionwas monitored by LCMS. Then the reaction mixture was passed through acelite bed and extracted with EtOAc (2×50 mL) and concentrated underreduced pressure to obtain the product, which was purified with reversephase HPLC to afford 169 mg of product4-[[2-(2-fluorophenyl)-5-isopropenyl-4-pyridyl]amino]-N-[(2S)-2-hydroxypropyl]pyridine-3-carboxamideas a white solid. The (R) enantiomer can be synthesized utilizing(R)-1-aminopropan-2-ol in Step-1.

¹HNMR: (400 MHz, CDCl₃): δ (ppm): 10.58 (bs, 1H), 8.75 (s, 1H), 8.42 (m,2H), 7.99 (m, 1H), 7.78 (s, 1H), 7.42 (d, 1H), 7.30 (m, 1H), 7.08 (t,1H), 6.92 (bs, 1H), 4.08 (m, 1H), 3.70 (m, 1H), 3.32 (m, 1H), 1.88 (m,1H), 1.30 (d, 3H), 1.18 (m, 2H), 0.75 (m, 2H).

Example 39. Preparation of Compound Nos. 39, 39a and 39b Synthesis of4-{[2-(3-chlorophenyl)-5-(prop-1-en-2-yl)pyridin-4-yl]amino}-N-[(2S)-2-hydroxypropyl]pyridine-3-carboxamide

Step-1: Synthesis of4-amino-N-[(2S)-2-hydroxypropyl]pyridine-3-carboxamide

See Example 37.

Step-2: Synthesis of 4-chloro-2-(3-chlorophenyl)-5-isopropenyl-pyridine

A 100 mL screw cap bottle was charged with2,4-dichloro-5-isopropenyl-pyridine (1.5 g, 8.0 mmol),2-fluorophenylboronic acid (837 mg, 6.0 mmol) and sodium carbonate (2.5g, 24.0 mmol) in a mixture of DME (20 mL) and water (5 mL) and degassedwith nitrogen for 15 min. Then Pd(PPh₃)₂.Cl₂ (280 mg, 0.40 mmol) andagain degassed with nitrogen for another 10 min. The resulting mixturewas heated at 100° C. for 3 h. The reaction was monitored by LCMS. Thenthe reaction mixture was passed through a celite bed, diluted with water(25 mL) and extracted with EtOAc (2×50 mL). The combined organic layerwas dried over anhydrous sodium sulfate and concentrated under reducedpressure. The crude product was passed through the CombiFlash®chromatography to afford 935 mg of product4-chloro-2-(3-chlorophenyl)-5-isopropenyl-pyridine as a colorless thickliquid.

Step-3: Synthesis of4-{[2-(3-chlorophenyl)-5-(prop-1-en-2-yl)pyridin-4-yl]amino}-N-[(2S)-2-hydroxypropyl]pyridine-3-carboxamide

A 25 mL screw cap bottle was charged with4-chloro-2-(3-chlorophenyl)-5-isopropenyl-pyridine (500 mg, 2.0 mmol)and 4-amino-N-[(2S)-2-hydroxypropyl]pyridine-3-carboxamide (433 mg, 2.2mmol) and K₃PO₄ (849 mg, 4.0 mmol) and 1,4-dioxane (10 mL) and degassedwith nitrogen for 15 min. Then xantphos (174 mg, 0.3 mmol) and Pd₂(dba)₃(183 mg, 0.2 mmol) were added and degassed with nitrogen for a further15 min. The resulting mixture was heated at 100° C. overnight. Theproduct formation was confirmed by LCMS. Then the reaction mixture waspassed through a celite bed and extracted with EtOAc (2×50 mL) extractedwith EtOAc (2×50 mL) and concentrated under reduced pressure to obtainthe product, which was purified with reverse phase HPLC to obtain 52 mgof4-[[2-(3-chlorophenyl)-5-isopropenyl-4-pyridyl]amino]-N-[(2S)-2-hydroxypropyl]pyridine-3-carboxamideas a white solid. The (R) enantiomer can be synthesized utilizing(R)-1-aminopropan-2-ol in Step-1.

¹HNMR: (400 MHz, CDCl₃): δ (ppm): 10.58 (bs, 1H), 8.75 (s, 1H), 8.42 (m,2H), 7.99 (m, 1H), 7.78 (s, 1H), 7.42 (d, 1H), 7.30 (m, 1H), 7.08 (t,1H), 6.92 (bs, 1H), 4.08 (m, 1H), 3.70 (m, 1H), 3.32 (m, 1H), 1.88 (m,1H), 1.30 (d, 3H), 1.18 (m, 2H), 0.75 (m, 2H).

Example 40. Preparation of Compound Nos. 40, 40a and 40b Synthesis ofN-[(2S)-2-hydroxypropyl]-4-{[5-(prop-1-en-2-yl)-2-[3-(trifluoromethyl)phenyl]pyridin-4-yl]amino}pyridine-3-carboxamide

Step-1: Synthesis of4-amino-N-[(2S)-2-hydroxypropyl]pyridine-3-carboxamide

See Example 37.

Step-2: Synthesis of4-chloro-5-isopropenyl-2-[3-(trifluoromethyl)phenyl]pyridine

A 100 mL screw cap bottle was charged with2,4-dichloro-5-isopropenyl-pyridine (800 mg, 4.26 mmol),[3-(trifluoromethyl)phenyl]boronic acid (606 mg, 3.19 mmol) and sodiumcarbonate (1.3g, 12.8 mmol) in a mixture of DME (5 mL) and water (2.5mL) and degassed with nitrogen for 15 min. Then Pd(PPh₃)₂.Cl₂ (147 mg,0.21 mmol) and again degassed with nitrogen for another 10 min. Theresulting mixture was heated at 100° C. for 3 h. The reaction wasmonitored by LCMS. Then the reaction mixture was passed through a celitebed, diluted with water (25 mL) and extracted with EtOAc (2×50 mL). Thecombined organic layer was dried over anhydrous sodium sulfate andconcentrated under reduced pressure to obtain the product, which waspurified by chromatography to obtain the product (250 mg) as an oil.

Step-3: Synthesis ofN-[(2S)-2-hydroxypropyl]-4-{[5-(prop-1-en-2-yl)-2-[3-(trifluoromethyl)phenyl]pyridin-4-yl]amino}pyridine-3-carboxamide

A 25 mL screw cap bottle was charged with4-chloro-5-isopropenyl-2-[3-(trifluoro methyl)phenyl]pyridine (250 mg,0.84 mmol) and 4-amino-N-[(2S)-2-hydroxypropyl]pyridine-3-carboxamide(180 mg, 0.92 mmol) and K₃PO₄ (356 mg, 1.7 mmol) and 1,4-dioxane (10 mL)and degassed with nitrogen for 15 min. Then xantphos (73 mg, 0.13 mmol)and Pd₂(dba)₃ (77 mg, 0.08 mmol) were added and degassed with nitrogenfor a further 15 min. The resulting mixture was heated at 100° C.overnight. The product formation was confirmed by LCMS. Then thereaction mixture was passed through a celite bed and extracted withEtOAc (2×50 mL) and concentrated under reduced pressure to obtain theproduct that was purified with reverse phase HPLC to obtain the product4-[[2-(3-chlorophenyl)-5-isopropenyl-4-pyridyl]amino]-N-[(2S)-2-hydroxypropyl]pyridine-3-carboxamideas a white solid (40 mg). The (R) enantiomer can be synthesizedutilizing (R)-1-aminopropan-2-ol in Step-1.

¹HNMR: (400 MHz, DMSO-d6): δ (ppm): 10.47 (bs, 1H), 8.86 (s, 1H), 8.48(m, 2H), 8.4-8.3 (m, 2H), 8.0 (s, 1H), 7.79 (d, 1H), 7.74-7.720 (m, 1H),7.44 (d, 1H), 5.44 (s, 1H), 5.18 (s, 1H) 4.78 (d, 1H), 3.80 (m, 1H),3.32 (m, 1H), 2.06 (s, 3H), 1.07 (d, 3H).

Example 41. Preparation of Compound No. 41 Synthesis ofN-[2-(5-chloro-2-fluorophenyl)-5-(prop-1-en-2-yl)pyridin-4-yl]quinolin-4-amine

Quinolin-4-amine (500 mg, 3.47 mmol) and4-chloro-2-(5-chloro-2-fluoro-phenyl)-5-isopropenyl-pyridine (1.1g, 3.82mmol) were dissolved in 5 mL dioxane. N, gas was purged for 10 min.Palladium acetate (78 mg, 0.347 mmol), xantphos (200 mg, 0.347 mmol),K₃PO₄ (2.2 g, 10.41 mmol) were added. Again N₂ gas was purged for 10min. The reaction was irradiated at 180° C. temperature for 30 min. Theprogress of reaction was monitored by LCMS. After completion ofreaction, the solvent was removed under reduced pressure. The residuewas diluted with 30 mL of water and extracted with DCM (3×50 mL). Thecombined organic layer was washed with water (2×20 mL), dried overanhydrous sodium sulfate and concentrated under reduced pressure. Thecrude product was purified by reverse phase HPLC to obtain 150 mg of thefree base ofN-[2-(5-chloro-2-fluoro-phenyl)-5-isopropenyl-4-pyridyl]quinolin-4-amine.

¹HNMR: (Free Base, CD₃OD): δ (ppm): 8.50 (m, 2H), 8.20 (d, 1H), 7.95 (d,1H), 7.90 (d, 1H), 7.80 (t, 1H), 7.60 (m, 2H), 7.42 (m, 1H), 7.20 (m,1H), 6.95 (bs, 1H), 5.30 (s, 2H), 2.05 (s, 3H).

Example 42. Preparation of Compound No. 42 Synthesis ofN-[2-(5-chloro-2-fluorophenyl)-5-(prop-1-en-2-yl)pyridin-4-yl]quinolin-5-amine

Quinolin-5-amine (300 mg, 2.10 mmol) and4-chloro-2-(5-chloro-2-fluoro-phenyl)-5-isopropenyl-pyridine (644 mg,2.30 mmol) were dissolved in 5 mL of dioxane. N₂ gas was purged for 10min. Palladium acetate (47 mg, 0.21 mmol), xantphos (127 mg, 0.21 mmol),K₃PO₄ (1.34 g, 6.30 mmol) were added. Again N₂ gas was purged for 10min. The reaction was irradiated at 180° C. temperature for 30 min.Progress of reaction was monitored by LCMS. After completion ofreaction, solvent was removed under reduced pressure. The residue wasdiluted with 30 mL of water and extracted with DCM (3×50 mL). Thecombined organic layer was washed with water (2×20 mL), dried overanhydrous sodium sulfate and concentrated under reduce pressure. Thecrude product was purified by reverse phase HPLC to obtain 25 mg freebase ofN-[2-(5-chloro-2-fluoro-phenyl)-5-isopropenyl-4-pyridyl]quinolin-5-amine.

¹HNMR: (Free Base, CD₃OD): δ (ppm): 8.95 (s, 1H), 8.30 (m, 3H), 7.90 (m,2H), 7.75 (t, 1H), 7.55 (m, 1H), 7.42 (m, 2H), 7.20 (t, 1H), 6.80 (s,1H), 5.40 (s, 1H), 5.30 (s, 1H), 2.15 (s, 3H).

Example 43. Preparation of Compound Nos. 43, 43a and 43b Synthesis of4-{[2-(5-chloro-2-fluorophenyl)-5-(propan-2-yl)pyridin-4-yl]amino}-N-[(2S)-1-hydroxybutan-2-yl]pyridine-3-carboxamide

Step-1: Synthesis of methyl2-[[2-(5-chloro-2-fluoro-phenyl)-5-isopropenyl-4-pyridyl]amino]pyridine-3-carboxylate

A 250 mL screw cap bottle was charged4-chloro-2-(5-chloro-2-fluoro-phenyl)-5-isopropenyl-pyridine (5 g, 17.7mmol), methyl 2-aminopyridine-3-carboxylate (4.0 g, 26.5 mmol),potassium phosphate tribasic (11.2 g, 53.1 mmol) and 1,4-dioxane (60mL). The resultant mixture was degassed with nitrogen for 15 min. To itwas added Pd₂dba₃ (811 mg, 0.88 mmol) and xantphos (1.02 g, 1.77 mmol)and again degassed with nitrogen for 15 min. The reaction mass washeated at 100° C. for 12 h. The reaction was monitored by LCMS. Thereaction mass was cooled to RT, diluted with DCM (20 mL) filteredthrough a small celite bed and concentrated under reduced pressure toobtain the product, which was purified by chromatography (eluent: 30%EtOAc in hexane) to obtain the pure methyl2-[[2-(5-chloro-2-fluoro-phenyl)-5-isopropenyl-4-pyridyl]amino]pyridine-3-carboxylate (2.1 g).

Step-2: Synthesis of2-[[2-(5-chloro-2-fluoro-phenyl)-5-isopropenyl-4-pyridyl]amino]-N-[(1S)-1-(hydroxymethyl)propyl]pyridine-3-carboxamide

A heterogeneous mixture of methyl2-[[2-(5-chloro-2-fluoro-phenyl)-5-isopropenyl-4-pyridyl]amino]pyridine-3-carboxylate(1 g, 2.5 mmol) and (S)-2-aminobutan-1-ol was irradiated by microwave at120° C. for 1 h. The reaction mass became a homogenous solution. Thereaction was monitored by LCMS and TLC. The reaction mass was purifiedby chromatography using combi flash (eluent: 5% methanol in DCM) toobtain2-[[2-(5-chloro-2-fluoro-phenyl)-5-isopropenyl-4-pyridyl]amino]-N-[(1S)-1-(hydroxymethyl)propyl]pyridine-3-carboxamide (500 mg).

Step-3: Synthesis of4-{[2-(5-chloro-2-fluorophenyl)-5-(propan-2-yl)pyridin-4-yl]amino}-N-[(2S)-1-hydroxybutan-2-yl]pyridine-3-carboxamide

To a solution of2-[[2-(5-chloro-2-fluoro-phenyl)-5-isopropenyl-4-pyridyl]amino]-N-[1-(hydroxymethyl)propyl]pyridine-3-carboxamide(500 mg, 1.09 mmol) in EtOAc (10 mL) and ethanol (5 mL) was addedplatinum oxide (90 mg 0.3 mmol) and bubbled with hydrogen gas for 3 h atRT. The reaction was monitored by ¹H NMR and TLC. The reaction mass wasfiltered through a celite bed and concentrated under reduced pressure toobtain the product, which was purified by chromatography two times(eluent: 3% methanol in DCM) to obtain pure4-{[2-(5-chloro-2-fluorophenyl)-5-(propan-2-yl)pyridin-4-yl]amino}-N-[(2S)-1-hydroxybutan-2-yl]pyridine-3-carboxamide(50 mg). This compound was converted to the HCl salt (46 mg). The (R)enantiomer can be synthesized utilizing (R)-2-aminobutan-1-ol in Step-2.

¹HNMR: (400 MHz, DMSO-d6): δ (ppm): 11.5 (bs, 1H), 9.0 (s, 1H), 8.9 (d,1H), 8.8 (s 1H), 8.38 (d, 1H), 8.0 (d, 1H), 7.78 (s, 1H), 7.76 (m, 1H),7.42 (t, 1H), 7.24 (d, 1H), 3.90 (m, 1H), 3.32 (m, 1H), 1.7 (m, 1H), 1.5(m, 1H), 1.30 (d, 6H), 0.9 (t, 3H).

Example 44. Preparation of Compound Nos. 44, 44a and 44b Synthesis of4-{[2-(5-chloro-2-fluorophenyl)-5-(trifluoromethyl)pyridin-4-yl]amino}-N-[(2S)-2-hydroxypropyl]pyridine-3-carboxamide

Step-1: Synthesis of4-chloro-2-(5-chloro-2-fluoro-phenyl)-5-(trifluoromethyl)pyridine

A two neck round bottom flask (100 mL) was charged with2,4-dichloro-5-(trifluoromethyl)pyridine (2.16 g, 10 mmol),(5-chloro-2-fluoro-phenyl)boronic acid (1.04 g, 6.0 mmol), sodiumcarbonate (3.18 g, 30 mmol), 1,2-dimethoxy ethane (20 mL) and water (4mL) degassed with nitrogen for 15 min. To it was addedbis(triphenylphosphine)palladium(II) dichloride (140 mg, 0.2 mmol) againdegassed with nitrogen for 10 min. The reaction mass was heated at 90°C. for 90 min. The reaction was monitored by LCMS. The reaction mass wascooled to RT, filtered through a small bed of celite, and diluted withEtOAc (50 mL) and water (50 mL). The layers were separated, aqueouslayer was again extracted with EtOAc (50 mL), the combined organics weredried over sodium sulfate and concentrated under reduced pressure toobtain the product, which was purified by chromatography (eluent:hexane) to obtain 1.2 g pure4-chloro-2-(5-chloro-2-fluoro-phenyl)-5-(trifluoromethyl)pyridine.

Step-2: Synthesis of4-{[2-(5-chloro-2-fluorophenyl)-5-(trifluoromethyl)pyridin-4-yl]amino}-N-[(2S)-2-hydroxypropyl]pyridine-3-carboxamide

A 25 mL screw cap bottle was charged with4-chloro-2-(5-chloro-2-fluoro-phenyl)-5-(trifluoromethyl)pyridine (500mg, 1.60 mmol), (S)-2-amino-N-(2-hydroxypropyl)benzamide (469 mg, 2.4mmol), potassium phosphate tribasic (1.02 g, 4.89 mmol) and 1,4-dioxane(20 mL). The resultant mixture was degassed with nitrogen for 15 min. Toit was added Pd₂dba₃ (74 mg, 0.08 mmol) and xantphos (93 mg, 0.160 mmol)and again degassed with nitrogen for 15 min. The reaction mass washeated at 100° C. for 12 h. The reaction was monitored by LCMS. Thereaction mass was cooled to room temperature, diluted with DCM (20 mL),filtered through a small celite bed and concentrated under reducedpressure to obtain the product, which was purified by chromatography andwith reverse phase HPLC to obtain the pure4-{[2-(5-chloro-2-fluorophenyl)-5-(trifluoromethyl)pyridin-4-yl]amino}-N-[(2S)-2-hydroxypropyl]pyridine-3-carboxamide(50 mg). The (R) enantiomer can be synthesized utilizing the(R)-2-amino-N-(2-hydroxypropyl)benzamide in this step.

¹HNMR: (400 MHz, CD₃OD): δ (ppm): 8.86-8.84 (d, 1H), 8.4 (d, 1H), 8.0(s, 2H), 7.56 (d, 1H), 7.50 (bs, 1H), 7.28 (t, 1H), 3.98 (m, 1H),3.43-3.41 (m, 2H), 1.25 (d, 3H).

Example 45. Preparation of Compound Nos. 45 Synthesis of4-{[2-(5-chloro-2-fluorophenyl)-5-(prop-1-en-2-yl)pyridin-4-yl]amino}-N-(oxetan-3-yl)pyridine-3-carboxamide

A heterogeneous mixture of methyl2-[[2-(5-chloro-2-fluoro-phenyl)-5-isopropenyl-4-pyridyl]amino]pyridine-3-carboxylate(500 mg, 1.25 mmol) and 3-oxetane amine (1 mL) was irradiated bymicrowave at 120° C. for 1 h. The reaction mass became a homogenoussolution. The reaction was monitored by LCMS and TLC. The reaction masswas purified by chromatography using combi flash (eluent: 5% methanol inDCM) to obtain the product, which was triturated with EtOAc to obtainpure4-{[2-(5-chloro-2-fluorophenyl)-5-(prop-1-en-2-yl)pyridin-4-yl]amino}-N-(oxetan-3-yl)pyridine-3-carboxamide(35 mg).

¹HNMR: (400 MHz, DMSO-d6): δ (ppm): 10.3 (s, 1H), 9.47 (d, 1H), 8.9 (s,1H), 8.46 (s, 1H), 8.41 (d, 1H), 8.0 (d, 1H,) 7.8 (s, 1H), 7.55 (m, 1H),7.40 (m, 2H), 5.46 (s, 1H), 5.19 (s, 1H), 5.0 (m, 1H), 4.7 (m, 2H), 4.6(m, 2H), 2.0 (s, 3H).

Example 46. Preparation of Compound Nos. 46, 46a and 46b Synthesis of4-{[2-(5-chloro-2-fluorophenyl)-5-(prop-1-en-2-yl)pyridin-4-yl]amino}-N-(oxolan-3-yl)pyridine-3-carboxamide

A heterogeneous mixture of methyl2-[[2-(5-chloro-2-fluoro-phenyl)-5-isopropenyl-4-pyridyl]amino]pyridine-3-carboxylate(250 mg, 0.62 mmol) and tetrahydrofuran-3-amine) was irradiated bymicrowave at 120° C. for 1 h. The reaction mass became a homogenoussolution. The reaction was monitored by LCMS and TLC. The reaction masswas purified by chromatography using combi flash (eluent: 5% methanol inDCM) to obtain product, which was triturated with EtOAc to obtain pure4-{[2-(5-chloro-2-fluorophenyl)-5-(prop-1-en-2-yl)pyridin-4-yl]amino}-N-(oxolan-3-yl)pyridine-3-carboxamide(17 mg) as a racemate. Chiral HPLC will resolve the enantiomers into theindividual (R) and (S) forms.

¹HNMR: (400 MHz, DMSO-d6): δ (ppm): 10.3 (s, 1H), 8.96 (d, 1H), 8.79 (s,1H), 8.44 (s, 1H), 8.40 (d, 1H), 8.0 (d, 1H,) 7.8 (s, 1H), 7.5 (m, 1H),7.4 (m, 2H), 5.48 (s, 1H), 5.2 (s, 1H), 4.46 (bs, 1H), 3.86-3.84 (m,2H), 3.7 (m, 1H), 3.6 (m, 1H), 2.1 (m, 1H), 2.0 (s, 3H), 1.9 (m, 1H).

Example 47. Preparation of Compound Nos. 47, 47a and 47b Synthesis of4-({2-[2-fluoro-5-(trifluoromethoxy)phenyl]-5-(prop-1-en-2-yl)pyridin-4-yl}amino)-N-[(2S)-2-hydroxypropyl]pyridine-3-carboxamide

Step-1: Synthesis of4-chloro-2-[2-fluoro-5-(trifluoromethoxy)phenyl]-5-isopropenyl-pyridine

A 100 mL screw cap bottle was charged with2,4-dichloro-5-isopropenyl-pyridine (800 mg, 4.26 mmol[4-fluoro-3-(trifluoromethoxy)phenyl]boronic acid (606 mg, 3.1 mmol) andsodium carbonate (1.3 g, 12.8 mmol) in a mixture of DME (5 mL) and water(2.5 mL) and degassed with nitrogen for 15 min. Then Pd(PPh₃)₂.Cl₂ (147mg, 0.21 mmol) and again degassed with nitrogen for another 10 min. Theresulting mixture was heated at 100° C. for 3 h. The reaction wasmonitored by LCMS. Then the reaction mixture was passed through a celitebed, diluted with water (25 mL) and extracted with EtOAc (2×50 mL). Thecombined organic layer was dried over anhydrous sodium sulfate andconcentrated under reduced pressure to obtain the product, which waspurified by chromatography to obtain4-chloro-2-[2-fluoro-5-(trifluoromethoxy)phenyl]-5-isopropenyl-pyridine(250 mg) as an oil.

Step-2: Synthesis of4-({2-[2-fluoro-5-(trifluoromethoxy)phenyl]-5-(prop-1-en-2-yl)pyridin-4-yl}amino)-N-[(2S)-2-hydroxypropyl]pyridine-3-carboxamide

A 25 mL screw cap bottle was charged with4-chloro-2-[2-fluoro-5-(trifluoro methoxy)phenyl]-5-isopropenyl-pyridine(250 mg, 0.84 mmol),4-amino-N-[(2S)-2-hydroxypropyl]pyridine-3-carboxamide (180 mg, 0.92mmol), K₃PO₄ (356 mg, 1.7 mmol) and 1,4-dioxane (10 mL) and degassedwith nitrogen for 15 min. Then Xantphos (73 mg, 0.13 mmol) and Pd₂(dba)₃(77 mg, 0.08 mmol) were added and the mixture degassed with nitrogen for15 min. The resulting mixture was heated at 100° C. overnight. Productformation was confirmed by LCMS. The reaction mixture was passed througha celite bed and extracted with EtOAc (2×50 mL) and concentrated underreduced pressure to obtain the product that was purified with reversephase HPLC to obtain4-({2-[2-fluoro-5-(trifluoromethoxy)phenyl]-5-(prop-1-en-2-yl)pyridin-4-yl}amino)-N-[(2S)-2-hydroxypropyl]pyridine-3-carboxamideas a free base (15 mg). The (R) enantiomer can be synthesized utilizing(R)-2-aminobutan-1-ol in this step.

¹H NMR: (400 MHz, DMSO-D6): δ (ppm): 10.42 (bs, 1H), 8.86 (m, 2H), 8.5(s, 1H), 8.4 (d, 2H), 8.0 (d, 1H), 7.90 (s, 1H), 7.58 (m, 2H), 7.40 (d,1H), 5.44 (s, 1H), 5.20 (s, 1H) 4.78 (d, 1H), 3.80 (m, 1H), 3.18 (m,1H), 2.06 (s, 3H), 1.07 (d, 3H).

Example 48. Preparation of Compound No. 48 Synthesis of4-{[2-(5-chloro-2-fluorophenyl)-5-(propan-2-yl)pyridin-4-yl]amino}-N-(oxetan-3-yl)pyridine-3-carboxamide

Step-1: Synthesis of methyl4-[[2-(5-chloro-2-fluoro-phenyl)-5-isopropyl-4-pyridyl]amino]pyridine-3-carboxylate

To a solution of methyl4-[[2-(5-chloro-2-fluoro-phenyl)-5-isopropenyl-4-pyridyl]amino]pyridine-3-carboxylate(398 mg, 1.0 mmol) in EtOAc (10 mL) and ethanol (5 mL) was addedplatinum oxide (60 mg, 0.2 mmol) and bubbled with hydrogen gas for 3 hat RT. The reaction was monitored by ¹H NMR and TLC. The reaction masswas filtered through a celite bed and concentrated under reducedpressure to obtain the product, which was purified by chromatography (5%MeOH in DCM) to obtain methyl4-[[2-(5-chloro-2-fluoro-phenyl)-5-isopropyl-4-pyridyl]amino]pyridine-3-carboxylate(180 mg).

Step-2: Synthesis of4-{[2-(5-chloro-2-fluorophenyl)-5-(propan-2-yl)pyridin-4-yl]amino}-N-(oxetan-3-yl)pyridine-3-carboxamide

A heterogeneous mixture of methyl4-[[2-(5-chloro-2-fluoro-phenyl)-5-isopropyl-4-pyridyl]amino]pyridine-3-carboxylate(180 mg, 0.45 mmol) and 3-oxitane amine (1 mL) was irradiated bymicrowave at 120° C. for 1 h. The reaction mass became a homogenoussolution. The reaction was monitored by LCMS and TLC. The reaction masspurified by chromatography (eluent: 5% MeOH in DCM) to obtain theproduct, which was triturated with EtOAc to obtain4-{[2-(5-chloro-2-fluorophenyl)-5-(propan-2-yl)pyridin-4-yl]amino}-N-(oxetan-3-yl)pyridine-3-carboxamide (10 mg).

¹H NMR: (400 MHz, DMSO-D6): δ (ppm): 10.5 (s, 1H), 9.47 (d, 1H), 8.9 (s,1H), 8.62 (s, 1H), 8.38 (d, 1H), 8.0 (d, 1H,) 7.8 (s, 1H), 7.55 (m, 1H),7.40 (m, 2H), 7.30 (d, 1H), 5.0 (m, 1H), 4.8 (t, 2H), 4.60 (t, 2H), 3.10(m, 1H), 1.24 (d, 6H).

Example 49. Preparation of Compound No. 49 Synthesis ofN-[2-(5-chloro-2-fluorophenyl)-5-(propan-2-yl)pyridin-4-yl]quinolin-4-amine

N-[2-(5-Chloro-2-fluoro-phenyl)-5-isopropenyl-4-pyridyl]quinolin-4-amine(100 mg, 0.257 mmol) was dissolved in EtOAc:EtOH (10 mL), and purgedwith N₂ gas for 10 min. PtO₂ (20 mg) was added, and the mixture nowpurged with H₂ gas for 10 min. The reaction was stirred at RT for 5 h.The progress of reaction was monitored by LCMS. After completion ofreaction, the PtO₂ was removed by filtration, and the solvent removedunder reduced pressure. The residue was purified by flash chromatographyusing MeOH:DCM to obtain 70 mg free base ofN-[2-(5-chloro-2-fluoro-phenyl)-5-isopropyl-4-pyridyl]quinolin-4-amine.

¹H NMR: (Free Base, CD₃OD): δ (ppm): 8.65 (m, 1H), 8.50 (s, 1H), 8.25(d, 1H), 7.95 (m, 1H), 7.85 (d, 1H), 7.75 (t, 1H), 7.60 (t, 1H), 7.50(s, 1H), 7.40 (m, 1H), 7.20 (t, 1H), 6.80 (s, 1H), 3.45 (m, 1H), 1.19(m, 6H).

Example 50. Preparation of Compound No. 50 Synthesis of2-N-[2-(5-chloro-2-fluorophenyl)-5-(prop-1-en-2-yl)pyridin-4-yl]-2-N-methylpyridine-2,4-diamine

Nitrogen gas was purged in a mixture of4-chloro-2-(5-chloro-2-fluoro-phenyl)-5-isopropenyl-pyridine (300 mg,1.06 mmol), N-2-methylpyridine-2,4-diamine (157 mg, 1.27 mmol) andpotassium phosphate (tribasic) (449 mg, 2.12 mmol) in 1,4-dioxane (15mL) for 15 min. Then tris(dibenzylidineacetone) dipalladium(0) (97 mg,0.12 mmol) and Xantphos (92 mg, 0.16 mmol) were added to the reactionmixture. Nitrogen gas was purged through it for another 5 min. Thereaction mixture was irradiated by microwave at 180° C. for 1 h. Thereaction was monitored by TLC and LCMS. After completion of reaction,the mixture was diluted with EtOAc (100 mL) and filtered through acelite bed. The filtrate was washed with water (25 mL), and the organiclayer was separated, dried over anhydrous sodium sulfate andconcentrated under reduced pressure to afford a crude product which waspurified by reverse phase purification to getN-2-[2-(5-chloro-2-fluoro-phenyl)-5-isopropenyl-4-pyridyl]-N-2-methyl-pyridine-2,4-diamine(Peak 1) as a semi-solid (26 mg) andN4-[2-(5-chloro-2-fluoro-phenyl)-5-isopropenyl-4-pyridyl]-N2-methyl-pyridine-2,4-diamine(Peak 2) (44 mg) as a white solid.

¹H NMR: (400 MHz, DMSO-d6): δ (ppm): 8.59 (s, 1H), 7.99 (s, 1H), 7.62(m, 2H), 7.59 (s, 1H), 7.38 (m, 1H), 6.00 (d, 1H), 5.70 (m, 3H), 5.15(m, 2H), 3.23 (s, 3H), 1.90 (s, 3H).

Example 51. Preparation of Compound Nos. 51, 51a and 51b Synthesis of4-{[2-(2,5-difluorophenyl)-5-(prop-1-en-2-yl)pyridin-4-yl]amino}-N-[(2S)-2-hydroxypropyl]pyridine-3-carboxamide

Step-1: Synthesis of2-(2,5-difluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

A 250 mL screw cap bottle was charged with 2-bromo-1,4-difluoro-benzene(1.0 g, 5.18 mmol), bis(pinacolato)diboroncarbonate and potassiumacetate (1.52 g, 15.54 mmol) in 1,4-dioxane (20 mL) and degassed withnitrogen for 20 min. Then Pd(dppf)Cl₂.DCM (634 mg, 0.77 mmol) was added,and the mixture again degassed with nitrogen for another 10 min. Theresulting mixture was heated at 100° C. overnight. The reaction wasmonitored by TLC and LCMS. The reaction mixture was passed through acelite bed, diluted with water (100 mL) and extracted with EtOAc (3×50mL) and washed with water (2×50 mL). The combined organic layer wasdried over anhydrous sodium sulfate and concentrated under reducedpressure to obtain the product, which was purified by chromatography toobtain 2-(2,5-difluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(500 mg) as a semisolid.

Step-2: Synthesis of4-chloro-2-(2,5-difluorophenyl)-5-isopropenyl-pyridine

A 100 mL screw cap bottle was charged with2,4-dichloro-5-isopropenyl-pyridine (1.5 g, 7.97 mmol) and to is wasadded 2-(2,5-difluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(2.29 mg, 9.57 mmol) and sodium carbonate (2.53 g, 23.91 mmol) in amixture of DME (15 mL) and water (7 mL), and the mixture degassed withnitrogen for 20 min. Then Pd(PPh₃)₂.Cl₂ (279 mg, 0.398 mmol) was addedand the mixture again degassed with nitrogen for another 10 min. Theresulting mixture was heated at 100° C. for 3 h. The reaction wasmonitored by TLC and LCMS. Then the reaction mixture was passed througha celite bed, diluted with water (50 mL) and extracted with EtOAc (4×150mL). The combined organic layer was washed with water (2×150 mL), driedover anhydrous sodium sulfate and concentrated under reduced pressure toobtain the product, which was purified with combiflash chromatography toobtain 4-chloro-2-(2,5-difluoro phenyl)-5-isopropenyl-pyridine (1.0 g)as a semi solid.

Step-3: Synthesis of4-{[2-(2,5-difluorophenyl)-5-(prop-1-en-2-yl)pyridin-4-yl]amino}-N-[(2S)-2-hydroxypropyl]pyridine-3-carboxamide

A 30 mL microwave vial was charged with4-chloro-2-(2,5-difluorophenyl)-5-isopropenyl-pyridine (500 mg, 1.886mmol), 4-amino-N-[(2S)-2-hydroxypropyl]pyridine-3-carboxamide (400 mg,2.07 mmol), K₃PO₄ (797 mg, 3.76 mmol) and 1,4-dioxane (10 mL) and themixture degassed with nitrogen for 20 min. Then Xantphos (163 mg, 0.28mmol) and Pd₂(dba)₃ (172 mg, 0.188 mmol) were added and degassed withnitrogen for a further 10 min. The resulting mixture was heated at 140°C. in a microwave. Product formation was confirmed by TLC and LCMS. Thereaction mixture was passed through a celite bed, diluted with water (50mL), extracted with EtOAc (2×100 mL) and washed with water (2×50 mL).The organic layer was dried over anhydrous sodium sulfate, andconcentrated under reduced pressure to obtain the product that waspurified by reverse phase HPLC to obtain4-{[2-(2,5-difluorophenyl)-5-(prop-1-en-2-yl)pyridin-4-yl]amino}-N-[(2S)-2-hydroxypropyl]pyridine-3-carboxamideas the free base (70 mg). The (R) enantiomer can be synthesizedutilizing the (R)-enantiomeric reagent in this step.

¹H NMR: (400 MHz, DMSO-D6): δ (ppm): 10.45 (bs, 1H), 8.82 (m, 2H), 8.45(s, 1H), 8.39 (d, 1H), 7.82 (s, 1H), 7.78 (bs, 1H), 7.42 (m, 2H), 7.39(m, 1H), 5.43 (s, 1H), 5.20 (s, 1H), 4.78 (d, 1H), 3.78 (m, 1H), 3.19(m, 2H), 2.06 (s, 3H), 1.12 (d, 3H).

Example 52. Preparation of Compound Nos. 52, 52a and 52b Synthesis of4-{[2-(2,5-difluorophenyl)-5-(propan-2-yl)pyridin-4-yl]amino}-N-[(2S)-2-hydroxypropyl]pyridine-3-carboxamide

To a solution of4-[[2-(2,5-difluorophenyl)-5-isopropenyl-4-pyridyl]amino]-N-[(2S)-2-hydroxypropyl]pyridine-3-carboxamide(50 mg, 0.117 mmol) in EtOAc (5 mL) and ethanol (5 mL) was addedplatinum oxide (20 mg, 0.2 mmol) and bubbled with hydrogen gas for 4 hat RT. The reaction was monitored by ¹H NMR and TLC. The reaction masswas filtered through a celite bed and concentrated under reducedpressure to obtain the product, which was purified by chromatography (5%MeOH in DCM) to obtain4-[[2-(2,5-difluorophenyl)-5-isopropyl-4-pyridyl]amino]-N-[(2S)-2-hydroxypropyl]pyridine-3-carboxamide (20 mg). The (R) enantiomer can besynthesized utilizing (R)-2-aminobutan-1-ol in this step.

¹H NMR: (400 MHz. CDCl₃): δ (ppm): 10.39 (s, 1H), 8.70 (s, 1H), 8.62 (s,1H), 8.39 (d, 1H), 7.79 (m, 2H), 7.28 (d, 1H,) 7.15 (m, 2H), 6.98 (bs,1H), 4.15 (m, 1H), 3.71 (m, 1H), 3.31 (m, 1H), 3.21 (m, 1H), 1.40 (d,6H), 1.21 (d, 3H).

Example 53. Preparation of Compound Nos. 53, 53a and 53b Synthesis of4-({2-[2-fluoro-5-(trifluoromethyl)phenyl]-5-(prop-1-en-2-yl)pyridin-4-yl}amino)-N-[(2S)-2-hydroxypropyl]pyridine-3-carboxamide

Step-1: Synthesis of4-chloro-2-[2-fluoro-5-(trifluoromethyl)phenyl]-5-isopropenyl-pyridine

A 100 mL screw cap bottle was charged with2,4-dichloro-5-isopropenyl-pyridine (1.0 g, 5.31 mmol),[2-fluoro-5-(trifluoromethyl)phenyl]boronic acid (1.65 g, 7.97 mmol) andsodium carbonate (1.68 g, 15.93 mmol) in a mixture of DME (10 mL) andwater (5 mL), and the mixture degassed with nitrogen for 20 min. ThenPd(PPh)₂.Cl₂ (186 mg, 0.265 mmol) and again degassed with nitrogen foranother 10 min. The resulting mixture was heated at 100° C. for 3 h. Thereaction was monitored by TLC and LCMS. Then the reaction mixture waspassed through a celite bed, diluted with water (50 mL) and extractedwith EtOAc (3×100 mL). The combined organic layer was washed with water(2×150 mL) dried over anhydrous sodium sulfate and concentrated underreduced pressure to obtain the product that was purified bychromatography to obtain4-chloro-2-[2-fluoro-5-(trifluoromethyl)phenyl]-5-isopropenyl-pyridine(500 mg) as a semi solid. Step-2: Synthesis of4-({2-[2-fluoro-5-(trifluoromethyl)phenyl]-5-(prop-1-en-2-yl)pyridin-4-yl}amino)-N-[(2S)-2-hydroxypropyl]pyridine-3-carboxamide

A 30 mL microwave vial was charged with4-chloro-2-[2-fluoro-5-(trifluoromethyl) phenyl]-5-isopropenyl-pyridine(500 mg, 1.58 mmol) and 4-amino-N-[(2S)-2-hydroxypropyl]pyridine-3-carboxamide (340 mg, 1.74 mmol) and K₃PO₄ (669 mg,3.16 mmol) and 1,4-dioxane (5 mL) and degassed with nitrogen for 20 min.Then Xantphos (137 mg, 0.237 mmol) and Pd₂(dba)₃ (144 mg, 0.158 mmol)were added and degassed with nitrogen for a further 10 min. Theresulting mixture was heated at 140° C. by microwave. Product formationwas confirmed by TLC and LCMS. Then the reaction mixture was passedthrough a celite bed and diluted with water (50 mL), extracted withEtOAc (2×100 mL) and washed with water (2×50 mL). The organic layer wasdried over anhydrous sodium sulfate and concentrated under reducedpressure to obtain the product that was purified by HPLC to obtain4-({2-[2-fluoro-5-(trifluoromethyl)phenyl]-5-(prop-1-en-2-yl)pyridin-4-yl}amino)-N-[(2S)-2-hydroxypropyl]pyridine-3-carboxamideas free base (30 mg). The (R) enantiomer can be synthesized utilizing(R)-2-aminobutan-1-ol in this step.

¹H NMR: (400 MHz, DMSO-D6): δ (ppm): 10.45 (bs, 1H), 8.82 (m, 2H), 8.45(s, 1H), 8.39 (d, 1H), 8.32 (d, 1H), 7.82 (bs, 2H), 7.61 (t, 1H), 7.41(d, 1H), 5.42 (s, 1H), 5.20 (s, 1H), 4.78 (d, 1H), 3.79 (m, 1H), 3.19(m, 2H), 2.06 (s, 3H), 1.12 (d, 3H).

Example 54. Preparation of Compound No. 54 Synthesis of4-{[2-(5-chloro-2-fluorophenyl)-5-cyclopropylpyridin-4-yl]amino}-N-(1,3-dihydroxypropan-2-yl)pyridine-3-carboxamide

Methyl4-[[2-(5-chloro-2-fluoro-phenyl)-5-cyclopropyl-4-pyridyl]amino]pyridine-3-carboxylate(100 mg, 0.251 mmol) and 2-aminopropane-1,3-diol (92 mg, 1.00 mmol) weredissolved in 1 mL of DMSO and heated at 120° C. in a microwave for 1.5h. Product formation was confirmed by LCMS. Then the reaction mixturewas diluted with water (50 mL), and the resultant precipitate filteredand dried. This crude product was purified by chromatography to obtain20 mg of4-[[2-(5-chloro-2-fluoro-phenyl)-5-cyclopropyl-4-pyridyl]amino]-N-[2-hydroxy-1-(hydroxymethyl)ethyl]pyridine-3-carboxamide.

¹H NMR: (400 MHz, DMSO-d6): δ (ppm): 10.78 (bs, 1H), 8.85 (s, 1H), 8.48(s, 1H), 8.40 (m, 2H), 7.98 (d, 1H), 7.80 (s, 1H), 7.55-7.42 (m, 2H),7.40 (t, 1H), 4.70 (t, 2H), 4.00 (m, 1H), 3.58 (m, 4H), 1.80 (m 1H),1.05 (m, 2H), 0.75 (n, 2H).

Example P1. Preparation of Compound Nos. 2.1 to 2.35

Compound nos. 2.1 to 2.35 can be prepared according to the methodspresented herein using appropriately functionalized starting materialsand reagents.

Example B1: p-SMAD2 Inhibition

Compounds of the invention were screened for inhibition of p-SMAD2,using Western Blot Analysis, using the following protocol. On Day 1,MDA-MB-231 cells were seeded at 150,000 cells/well in a 12-well plateusing DMEM plus antibiotics (Pen/Strepto) plus FBS 10%. On Day 2, themedium was changed to a serum-free version (DMEM plus Ab) and leftovernight. On Day 3, the cells were treated with Compounds of theinvention for 30 min (pre-treatment) at two concentrations of 0.1 μM and0.5 μM (prepared with serum-free medium). Then. TGFβ was added to afinal concentration of 2 ng/mL for 1.5 h.

Western Blot Analysis: Lysis buffer plus proteases and phosphatiseinhibitors were added to the cells (100 μL), then the cells werecollected with a cell scraper and placed into an Eppendorf tube. Thesample was sonicated for 3 min, then centrifuged for 15 min at 13,000rpm at 4° C. The proteins were quantified with the BCA Protein Assay Kit(Pierce, #23225), and SDS-PAGE electrophoresis with 10% acrylamide gelwas used to separate the samples (20 μg of protein loaded). The proteinswere transferred in a PDVF membrane overnight at 50 mA and 4° C., thenthe membrane was blocked with 5% milk solution for 1 h. The primaryantibody was added (p-SMAD2, cell signalling #3108: SMAD2, cellsignalling #3103: or β-Actin, Sigma #A5441) at 4° C. overnight, or for 2h at RT. The membrane was washed with TBS-TWEEN® (0.1%) three times over10 min. The second antibody was added for h at RT, and then the membranewashed again with TBS-TWEEN® (0.1%) for 10 min. Signal development wasperformed using an ECL Western Blotting Substrate (Pierce #32106), andthe image acquired using the Gel Logic 6000 Pro. Quantification wasperformed using ImageJ software, and the average % inhibition wasobtained and presented in Table B1.

TABLE B1 Inhibition of p-SMAD (samples run in triplicate) Averagep-SMAD2 Average p-SMAD2 Compound inhibition inhibition Number @ 0.1 μM(% Inh) @ 0.5 μM (% Inh) CE-1 15.67 17.00  1a 31.33 64.33  2a 26.3377.67  3a 45.67 78.00  4a 72.67 99.67  5a 14.33 41.33  6a 53.67 98.33 7a 74.33 99.33  7b 36.33 78.67  8 58.67 94.33  9 6.00 12.67 10a 0 64.3311a 44.67 96.00 12a 64.33 93.00 13a 59.00 93.67 14 45.00 92.33 15 80.3397.33 16a 58.33 88.00 17a 25.33 81.67 18 31.33 82.67 19 74.67 93.00 20a0 3.67 21a 4.67 7.67 22 50.00 93.67 23a 46.33 93.67 24a 17.00 68.33 25a15.33 18.67 25b 14.33 12.67 26 64.00 89.00 27 29.33 81.33 28 2.33 51.3329 58.00 67.67 30 59.67 70.33

Example B2: In Vitro Kinase Assay—Inhibition of ALK1/2/3/4/5/6 Kinases

Compound of the invention were screened in an in vitro kinase assayagainst several members of the TGFβ family of Ser/Thr kinases. Thekinases tested were ALK1 (ACVRL1), ALK2 (ACVR1), ALK3 (BMPR1A), ALK4(ACVR1B), ALK5 (TGFBR1), and ALK6 (BMPR1B). Standard kinase testingconditions and techniques were employed. For each case, specifickinase/substrate pairs along with required cofactors were prepared inreaction buffer. Compound of the invention were delivered into thereaction, followed 15-20 min later by addition of a mixture of ATP and³³P ATP to a final concentration of 10 μM. Reactions were carried out atRT for 120 min, followed by spotting of the reactions onto P81 ionexchange filter paper. Unbound phosphate was removed by extensivewashing of filters in 0.75% phosphoric acid. Kinase activity data wasexpressed as the percent of remaining kinase activity in test samplescompared to vehicle. IC₅₀ values were generated from activity valuesperformed at multiple concentrations, and the results are presented inTable B2.

TABLE B2 In vitro Kinase Assay Inhibition Inhibition InhibitionInhibition Inhibition Inhibition of ALK1 of ALK2 of ALK3 of ALK4 of ALK5of ALK6 Compound (IC₅₀ (IC₅₀ (IC₅₀ (IC₅₀ (IC₅₀ (IC₅₀ Number μM) μM) μM)μM) μM) μM) CE-1 >100 >100 >100 >100 >100 >100 1a >100 >100 >100 93.20.25 >100 2a 10 >100 >100 0.0325 0.0204 >100 3a 8.41 >100 >100 0.03150.0452 >100 4a 3.44 10.6 >100 0.0424 0.0281 — 6a 5.01 10.4 >100 0.00860.0157 — 7a 6.57 10.9 >100 0.0130 0.0162 — 7b 16.50 >100 >100 0.17100.0539 >100 8 >100 >100 >100 0.5020 0.0992 — 11a 6.75 >100 >100 0.08680.0335 — 12a 1.53 9.97 >100 0.0304 0.0175 — 13a 9.12 >100 >100 0.02350.0715 — 14 5.85 >100 >100 0.0451 0.0239 — 15 4.59 11.4 15.4 0.01170.0155 — 16a 7.3 >1000 >1000 0.1140 0.0422 >1000 17a 4.67 >1000 >10000.0401 0.0508 >1000 18 6.92 >1000 >1000 0.1050 0.0345 >1000 192.13 >1000 >1000 0.0110 0.0068 >100020a >100 >1000 >1000 >1000 >100 >100021a >100 >1000 >1000 >1000 >100 >1000 22 7.29 >1000 >1000 0.05670.0247 >1000 23a 5.67 >100 >100 0.0331 0.0169 >100 24a >100 >100 >1000.2300 0.0653 >100 25a >100 >100 >100 >100 2.8000 >10025b >100 >100 >100 5.02 0.9880 >100 26 5.20 >100 >100 0.0115 0.0103 >10027 13.10 >100 >100 0.0402 0.0281 >100 28 >100 >1000 >1000 1.10000.5510 >1000 29 8.20 60.60 >10 0.0105 0.0164 15.30 30 5.90 73.00 >100.0237 0.0264 13.50 31 >10 >10 >10 0.0048 0.0105 >10 32 2.54 5.84 3330.0027 0.0061 >10 33 >10 >10 >10 0.0896 0.0788 >10 34 >10 >10 >10 0.14900.0773 >10 35 1.94 5.45 871 0.0037 0.0082 9.62 36 3.7 8.93 >10 0.00370.0177 >10

Example B3: Pharmacokinetics and Bioavailability for Compounds of theInvention

The pharmacokinetics and bioavailability of compounds in male mice weredetermined after a single dose, administered either intravenously (2mg/kg) or orally (10 mg/kg). Compounds were formulated at 1 mg/mL in 50%PEG-400 or 20% HPβCD. Parameters were generated using WinNonlinnon-compartment analysis with no weighting, and are presented in TablesB3a and B3b.

TABLE B3a Intravenous Administration, 2 mg/kg, n = 3 mice/timepoint,Terminal Compound C_(max) AUC_(last) t_(1/2) CL V No. (μM) (μM*h) (h)(L/h/kg) (L/kg)  2a 0.544 1.19 1.80 1.60 4.14  3a 0.602 2.56 3.86 0.771.29  8 1.24 0.709 1.68 6.15 14.9 11a 3.61 3.15 1.02 1.48 2.17 12a 7.153.69 1.63 1.19 2.80 13a 1.42 1.56 2.09 1.24 3.72 14 3.01 1.57 0.987 2.713.86 16a 3.40 4.41 0.655 1.02 0.967 19 0.52 1.19 6.12 2.39 21.1 22 2.463.77 1.53 1.10 2.43 23a 2.56 1.11 0.607 3.96 3.47 26 3.00 1.76 1.62 2.666.21

TABLE B3b Oral Administration, 10 mg/kg Compound C_(max) T_(max)AUC_(last) Terminal No. (μM) (h) (μM*h) t_(1/2) (h) Bioavailability  2a1.57 0.5 5.25 2.57   88%  3a 1.65 0.25 10.5 3.85   82%  8 1.06 0.25 1.311.26 36.9% 11a 3.48 0.25 9.79 1.65 62.2% 12a 4.28 0.5 14.5 1.72 78.3%13a 1.60 0.25 5.64 2.85 72.3% 14 1.88 0.5 2.54 1.60 32.5% 16a 3.42 0.57.50 2.36 34.1% 19 0.198 1 0.927 4.19 15.5% 22 7.07 0.5 16.2 2.09 86.6%23a 0.612 0.25 0.907 0.822 16.4% 26 1.29 0.5 2.36 1.66 26.9%

Plasma and brain concentrations of compounds at 0.5 and 1 h were alsoanalyzed and are presented in Tables B3c and B3d.

TABLE B3c Plasma and brain concentrations (mg/mL) IV (2 mg/kg) PO (10mg/kg) Compound Time % % No. (h) Plasma Brain Brain Plasma Brain Brain2a 0.5 310 73.2 24 1570 202 13 1 366 82.4 23 905 114 13 3a 0.5 432 17340 1280 305 24 1 365 168 46 1250 406 32

TABLE B3d Plasma and brain concentrations (μM). Brain Plasma CompoundTime Concentration Concentration % of No. Route (h) (μM) μM) Plasma 16aIV 0.5 0.048 3.04 1.58% 1 0.019 1.23 1.52% PO 0.5 0.048 3.42 1.40% 10.025 1.69 1.50% 19 IV 0.5 0.004 0.280 1.49% 1 0.003 0.183 1.80% PO 0.5BLQ 0.164 na 1 BLQ 0.198 na 22 IV 0.5 0.007 1.69 0.41% 1 0.005 0.9670.48% PO 0.5 0.020 7.07 0.29% 1 0.015 3.53 0.43%

It is understood that the foregoing examples and embodiments describedabove are for illustrative purposes only and that various modificationsor changes in light thereof will be suggested to persons skilled in theart and are to be included within the spirit and purview of thisapplication and the scope of the appended claims.

The invention claimed is:
 1. A method of providing a first or a secondline therapy for treating (a) a breast cancer in an individual diagnosedwith the breast cancer or (b) a prostate cancer in an individualdiagnosed with the prostate cancer, comprising administering to theindividual an effective amount of

4-(2-(5-chloro-2-fluorophenyl)-5-isopropylpyridin-4-ylamino)-N-(1,3-dihydroxypropan-2-yl)nicotinamideor a pharmaceutically acceptable salt thereof, thereby decreasing numberof cancer cells, inhibiting cancer cell growth and/or proliferation, orincreasing apoptosis of cancer cells.
 2. The method of claim 1, whereinthe individual is diagnosed with the breast cancer.
 3. The method ofclaim 2, wherein the breast cancer is selected from the group consistingof ER negative breast carcinoma, ER positive breast carcinoma, primarybreast ductal carcinoma, mammary adenocarcinoma, ER positive mammaryductal carcinoma, ER negative mammary ductal carcinoma, HER2 positivemammary ductal carcinoma, HER2 positive breast cancer, luminal breastcancer, triple negative breast cancer (TNBC), and unclassified breastcancer.
 4. The method of claim 3, wherein the breast cancer is TNBC, andthe TNBC is selected from the group consisting of basal-like TNBC,mesenchymal TNBC, mesenchymal stem-like TNBC, immunomodulatory TNBC, anda luminal androgen receptor TNBC.
 5. The method of claim 3, wherein thebreast cancer is a luminal breast cancer.
 6. The method of claim 1,wherein the individual is diagnosed with the prostate cancer.
 7. Themethod of claim 6, wherein the prostate cancer is prostateadenocarcinoma.
 8. The method of claim 1, wherein the treating comprisesa reduction of tumor size.
 9. The method of claim 1, wherein thetreating comprises a slowing of tumor growth.
 10. The method of claim 1,wherein the treating comprises slowing of metastasis.
 11. The method ofclaim 1, further comprising administering to the individual a secondcancer therapy.
 12. The method of claim 11, wherein the second cancertherapy comprises a therapy selected from the group consisting ofsurgery, radiation, and chemotherapy.
 13. The method of claim 12,wherein the second cancer therapy is a chemotherapy.
 14. The method ofclaim 13, wherein the individual is diagnosed with the breast cancer.15. The method of claim 14, wherein the breast cancer is a luminalbreast cancer.
 16. The method of claim 14, wherein the breast cancer isTNBC.
 17. The method of claim 13, wherein the individual is diagnosedwith the prostate cancer.
 18. The method of claim 17, wherein theprostate cancer is prostate adenocarcinoma.
 19. The method of claim 1,wherein the pharmaceutically acceptable salt is a hydrochloride salt.